Erdafitinib in BCG-treated high-risk non-muscle-invasive bladder cancer.

BACKGROUND: Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette-Guérin (BCG) treatment and who are ineligible for/refuse radical cystectomy. FGFR alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select FGFR3/2 alterations following recurrence after BCG treatment. PATIENTS AND METHODS: Patients aged ≥18 years with recurrent, BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy were randomized to 6 mg daily oral erdafitinib or investigator's choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint was recurrence-free survival (RFS). The key secondary endpoint was safety. RESULTS: Study enrollment was discontinued due to slow accrual. Seventy-three patients were randomized 2 : 1 to erdafitinib (n = 49) and chemotherapy (n = 24). Median follow-up for RFS was 13.4 months for both groups. Median RFS was not reached for erdafitinib [95% confidence interval (CI) 16.9 months-not estimable] and was 11.6 months (95% CI 6.4-20.1 months) for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal P value = 0.0008). In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy. CONCLUSIONS: Erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after BCG therapy and refused or were ineligible for radical cystectomy.

Clinical characteristics and factors associated with survival rate of patients with non-muscle invasive bladder cancer attending at a Tertiary Hospital in Somalia.

BACKGROUND: A few studies regarding the epidemiology and risk factors of Non-muscle Invasive Bladder Cancer (NMIBC) are reported from Sub-Saharan African countries (SSA), including Somalia, and the African literature is scant on the management of NMIBC. The present study aims to evaluate the clinical-histopathological characteristics and factors associated with the survival rate of patients with NMIBC. METHOD: This six-year cohort study included 196 patients with NMIBC. It reviewed the clinical and histopathological characteristics and factors predicting cancer-specific survival for these patients. RESULTS: The mean patient age was 59.01 ± 11.50 years, with a male-to-female ratio of 2.8:1. Urothelial carcinoma (UC) constituted the most common pathological type, accounting for 90.8%; Ta LG and T1HG were the most common histopathological tumour stage and grade (n = 90, 45.9%, vs. n = 56, 28.6%), respectively. The mean tumour size was 4.72 ± 2.81 cm. The cancer-specific mortality(CSM) was 13.3%. Age [2.252(2.310-2.943], p < 0.001], Gender [1.031(0.981-1.1.242),p < 0.001], tumour stage and grade [4.902(3.607-5.614),p < 0.001], tumour location [1.135(0.806-1.172),p < 0.001], number [0.510(0.410-0.920),p = 0.03], tumour size [1.523(0.936-1.541),p < 0.001], use of intravesical chemotherapy or BCG [2.810(1.972-4.381),p < 0.001], preoperative hydronephrosis grade [1.517(1.172-2.154),p < 0.001], and follow-up compliance [3.376(2.633-5.018),p < 0.001] were all associated with CSM. The 5-year overall survival was 57.1%, and cardiovascular diseases were the leading cause of mortality (n = 34), followed by diabetes (n = 28). CONCLUSION: Our study findings revealed that UC constituted the most common pathological subtype, though less than forty per cent of our patients receive intravesical adjuvant therapies, which are crucial to minimizing disease morbidity and mortality. Initiatives improving uro-oncological care, including subspecialty training in oncology and essential cancer therapies, better access to urology services, and cancer screening programs, are much needed for optimal management plans and care in the country.

Efficacy and tolerance of hyperthermic intravesical chemotherapy (HIVEC) according to the number of instillations administered.

PURPOSE: To report the oncological outcomes and the tolerance between 6 instillations and more than 6 cycles of hyperthermic intravesical chemotherapy(HIVEC) in patients with non-muscle invasive bladder cancer(NMIBC). METHODS: This is a multicenter retrospective study from a national database including 9 expert centers. All patients treated with HIVEC between 2016 and 2023 for NMIBC were included. Patients were classified into two groups according to the total number of HIVEC instillations, including induction plus maintenance. Kaplan-Meier curves were computed to present survival outcomes. RESULTS: 261 patients with a median follow-up of 25.5 months were included. 199(76.2%) and 62(23.8%) were treated by 6 and more than 6 cycles of HIVEC, respectively. The 2-years RFS(40.2% vs. 34.4%,p = 0.3) and the 2-years PFS(86% vs. 87%,p = 0.85) were similar between group treated with 6 and more than 6 instillations. 2-years CSS and OS were also similar between both groups. Univariate Cox regression showed no association between the number of bladder instillation and RFS (HR = 1.2 95%CI[0.8-1.84], p = 0.3) or PFS (HR = 0.8 95%CI[0.29-2.02], p = 0.2). In the group treated with more than 6 cycles, 2-years RFS and 2-years PFS were similar between patients who received induction plus maintenance compared to those treated with induction only. Finally, hematuria and urinary burning were significantly higher in the group treated by more than 6 cycles (21% vs. 8.5%(p < 0.01),and 29% vs. 17% (p = 0.03), respectively). Serious side effects(grade ≥ 3) are rare(3.1%) and similar in both groups. CONCLUSIONS: Results show no significant difference in two years RFS, PFS, CSS and OS according to number of instillations received, while toxicity profile seems better in the group receiving six instillations only.

Is switching intravesical chemotherapeutic agents beneficial in short-term recurrent high-risk non-muscle-invasive bladder tumors? A 5-year retrospective study.

OBJECTIVE: To explore if switching intravesical chemotherapeutic agents is beneficial in short-term recurrences of high-risk non-muscle-invasive bladder cancer (NMIBC) following the failure of preceding intravesical therapy. MATERIALS AND METHODS: From June 2010 to October 2015, 205 patients with NMIBC who experienced tumor recurrence within a year after receiving first-line intravesical chemotherapy (IVC) were classified into two groups. After a second complete transurethral resection (TUR) process, we immediately altered the intravesical instillation agent for 107 patients (group A). In contrast, the remaining 98 patients (group B) continued using their original intravesical instillation agent. After transurethral resection of the bladder tumor (TURBT), all patients received either an immediate instillation of epirubicin (EPI), gemcitabine (GEM), or hydroxycamptothecin (HCPT), followed by regular induction and maintenance instillations. Recurrence and progression rates were evaluated using the Chi-square test, and recurrence-free survival (RFS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. RESULTS: In this study, there was no significant difference in either the 5-year tumor recurrence or progression rates between the two groups (p > 0.05) The Kaplan-Meier plot showed no difference in progression-free or recurrence-free survival between the two groups. CONCLUSION: Switching IVC agents does not improve RFS and PFS for patients with short-term recurrent high-risk NMIBC.

Evaluation of toxicities for intravesical drugs in phase 1 bladder cancer trials.

BACKGROUND: Improving clinical trial design is important for optimizing approval of safe and effective drugs. Phase 1 clinical trials seek to determine phase 2 doses by investigating predefined dose-limiting toxicities. Traditional definitions of dose-limiting toxicity may not be applicable to intravesical therapies for bladder cancer. This study compared the frequency of dose-limiting toxicities and serious adverse events in bladder cancer trials for intravesical therapies to other routes of administration. METHODS: Studies were abstracted from ClinicalTrials.gov and reconciled with a PubMed search. Primary and secondary end points were predefined before data abstraction, and the primary end point was subject-level dose-limiting toxicity rate. Fisher exact tests were performed with p < .05 designated as significant. RESULTS: Eighteen intravesical studies and 24 studies with other routes of administration (the per os/intravenous/intramuscular [PO/IV/IM] group) were identified. Dose-limiting toxicities were reported in 38.9% of intravesical studies, affecting 3.29% of subjects, compared with 30.0% of PO/IV/IM studies representing 4.19% of subjects (p = .52 for study-level and p = .60 for subject-level comparisons). Serious adverse events occurred in 53.9% of intravesical studies in 10.3% of subjects versus 91.0% of studies reporting serious adverse events affecting 41.4% of subjects in the PO/IV/IM group (p = .03 for subject-level and p < .0001 for study-level comparisons). CONCLUSIONS: There was no difference in subject-level dose-limiting toxicity rate between intravesical and PO/IV/IM bladder cancer trials. The serious adverse event rate was lower in the intravesical group. Heterogeneity of dose-limiting toxicity definition may affect interpretation of toxicity in phase 1 bladder cancer clinical trials studying different routes of administration. LAY SUMMARY: Bladder cancer is a common cancer type that may be treated with therapies that are instilled into the bladder and act locally, called intravesical therapies. This study used publicly available regulatory data from early phase clinical trials to determine whether measures of tolerability used in clinical trials are applicable to intravesical therapies for bladder cancer.

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

OBJECTIVE: Although 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 METHODS: This 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). RESULTS: The 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. CONCLUSIONS: In 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.

A 6-month maintenance schedule of mitomycin C after radical nephroureterectomy for upper tract urothelial carcinoma for the prevention of intravesical recurrence: a retrospective, single center study.

PURPOSE: To show the effect of a 6-month (4 times weekly followed by 5 times monthly) maintenance mitomycin C regimen on the prevention of intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). METHODS: A total of 119 patients undergoing a RNU between 2007 and 2021 in a single center hospital were retrospectively reviewed. A total of 66 patients were eligible for further analysis. 27 patients received no post-operative MMC (median follow-up: 110 months) and 39 patients received a 6-month (4 times weekly, 5 times monthly) maintenance regimen of MMC (median follow up: 48 months). The primary outcome was the 1-, 2- and 5-year bladder recurrence free survival (BRFS). RESULTS: There was a significant difference (p = 0.001) in BRFS between the two groups. The 1-, 2, and 5-year BRFS for the MMC- group was 67%, 63% and 43%, respectively. The 1-, 2- and 5-year BRFS for the MMC + group was 95%, 86% and 86%, respectively. Univariate analysis showed no other potential prognostic factors that had a significant effect on the BRFS. CONCLUSION: A 6-month maintenance schedule of MMC is effective at significantly reducing the risk of IVR after RNU for UTUC. We could not find any other significant prognostic factors to predict IVR.

Novel Therapies for High-Risk Non-Muscle Invasive Bladder Cancer.

PURPOSE OF REVIEW: The treatment options for high-risk non-muscle invasive bladder cancer (NMIBC), particularly following BCG, remain limited. We highlight recent, promising therapies for high-risk NMIBC. RECENT FINDINGS: Several therapies utilizing different mechanisms of action have demonstrated favorable results in the BCG-naïve and BCG-unresponsive settings. These treatments include intravenous and intravesical immunotherapy, viral- and bacterial-based intravesical therapies, combination intravesical chemotherapy regimens, and novel intravesical chemotherapy administration. Overall, the efficacy and tolerability of emerging treatments for NMIBC appear promising and provide potential alternatives to radical cystectomy. As the landscape of managing BCG-unresponsive disease evolves, clinical trials will explore future options and determine effective alternatives.

Development and investigation of a novel device with gemcitabine for hyperthermic intravesical chemotherapy.

PURPOSE: To evaluate the safety and efficacy of a novel hyperthermic intravesical chemotherapy (HIVEC) device in combination with gemcitabine. MATERIALS AND METHODS: A pilot clinical trial was performed on patients with high-risk non-muscle invasive bladder cancer (NMIBC), who received HIVEC via the novel device (BR-PRG). Treatment regimen included eight weekly instillations of intravesical GEM (3 g in 150 mL normal saline [NS]) at a temperature of 45 °C for 60 min. Assessment of adverse events (AEs) was the primary objective of the trial. Disease recurrence and the thermal stability of GEM were also analyzed. RESULTS: A total of 116 HIVEC treatments were delivered. Fifteen and eighteen patients were included in the effectiveness and safety analysis, respectively. Median follow-up was 12 months; five patients experienced a disease recurrence. One-year cumulative incidence of recurrence was 23.8% in EORTC intermediate risk group and 37.5% in high-risk group. Ten patients experienced at least one AE, with the most common being acute urinary tract infection, followed by urinary tract pain, and hematuria. Two patients experienced acute cystitis (grade 3 AE) and instillations were postponed until full recovery. Other AEs were minor, and no systemic toxicity was observed. The contents of GEM in solution of 0.9% NS or NS mixed with artificial urine were stable at 25 °C, 37 °C, 43 °C, 45 °C, 47 °C and 50 °C for 2 h. CONCLUSION: GEM can be an ideal drug for use in HIVEC due to its good thermal stability. BR-PRG, combined with GEM was safe and effective in administering HIVEC.

Evaluation of thermal dose effect in radiofrequency-induced hyperthermia with intravesical chemotherapy for nonmuscle invasive bladder cancer.

PURPOSE: In nonmuscle invasive bladder cancer (NMIBC) patients who fail standard intravesical treatment and are unfit or unwilling to undergo a radical cystectomy, radiofrequency (RF)-induced hyperthermia combined with intravesical chemotherapy (RF-CHT) has shown promising results. We studied whether higher thermal dose improves clinical NMIBC outcome. METHODS AND MATERIALS: The cohort comprised 108 patients who started with RF-CHT between November 2013 and December 2019. Patients received intravesical mitomycin-C or epirubicin. Bladder hyperthermia was accomplished with an intravesical 915 MHz RF device guided by intravesical thermometry. We assessed the association between thermal dose parameters (including median temperature and Cumulative Equivalent Minutes of T50 at 43 °C [CEM43T50]) and complete response (CR) at six months for patients with (concomitant) carcinoma in situ (CIS), and recurrence-free survival (RFS) for patients with papillary disease. RESULTS: Median temperature and CEM43T50 per treatment were 40.9 (IQR 40.8-41.1) °C and 3.1 (IQR 0.9-2.4) minutes, respectively. Analyses showed no association between any thermal dose parameter and CR or RFS (p > 0.05). Less bladder spasms during treatment sessions was associated with increased median temperature and CEM43T50 (adjusted OR 0.01 and 0.34, both p < 0.001). CONCLUSIONS: No significant association between thermal dose and NMIBC outcome was found. Possibly thermal dose effect in patients of the current cohort exceeds a certain threshold value. On the other hand, occurrence of bladder spasms had a thermal dose limiting effect. We advise to treat patients with temperatures >40.5 °C for at least 45 min while respecting individual tolerability, including occurrence of bladder spasms.

Molecular classification of patients with NMIBC predicts the efficacy of intravesical chemotherapy with pirarubicin, pharmorubicin and gemcitabine-immunohistochemistry-based classification.

OBJECTIVE: To investigate the relationships between non-muscle invasive bladder cancer molecular subtypes and predict the efficacy of intravesical chemotherapy with pirarubicin, pharmorubicin and gemcitabine. METHODS: A total of 160 patients with T1 stage non-muscle invasive bladder cancer were enrolled in this study. Fifty-three patients underwent anthracycline (Pirarubicin and Pharmorubicin) therapy and 107 patients accepted gemcitabine therapy. Uroplakin II and CK20 were categorized as immunohistochemistry (IHC) markers for luminal subtype, whereas CK5/6 and CD44 were categorized as immunohistochemistry markers for basal subtype. The cluster results with immunohistochemical score indicated that non-muscle invasive bladder cancer can be subgrouped into three major classes. RESULTS: Class 2 showed the luminal-like characteristics, whereas class 3 showed the basal-like characteristics. Class 1 showed no high expression of luminal or basal-associated immunohistochemistry markers. The molecular subtype is an independent risk factor for recurrence-free survival (P = 0.030) and progression-free survival (P = 0.006) in patients with T1 stage non-muscle invasive bladder cancer. In class 1 and class 2 (luminal-like) subtypes, gemcitabine and anthracycline show no difference in recurrence-free survival and progression-free survival. Gemcitabine was associated with reduced recurrence compared with anthracycline (P = 0.039) in class 3 (basal-like) subtypes and show no difference in decreasing progression. CONCLUSIONS: The molecular classification based on immunohistochemical results is an independent risk factor for the prognosis of non-muscle invasive bladder cancer with T1 stage. Different therapeutic methods should be selected according to different molecular subtypes.

Tumor-targeting albumin nanoparticles as an efficacious drug delivery system and potential diagnostic tool in non-muscle-invasive bladder cancer therapy.

Current intravesical chemotherapy for non-muscle invasive bladder cancer (NMIBC) has limited efficacy due to loss of the instilled agent from urine voiding and the agent's lack of specificity for the tumors. We developed a nanocarrier (txCD47-HNP, ∼100 nm) based on human serum albumin conjugated with a peptide that targets the cluster of differentiation 47 receptor overexpressed on bladder cancer (BC) cells. The IC50 of gemcitabine elaidate (GEM) loaded in the txCD47-HNP was almost an order of magnitude lower than that of free GEM. In a mouse orthotopic BC model, GEM loaded in txCD47-HNP effectively reduced the tumor burden. Tumor cells in BC patients' urine can also be targeted by fluorescence-labeled txCD47-HNP resulting in >83 % of the cells exhibiting fluorescence. Thus, txCD47-HNP can potentially be a theranostic agent in NMIBC management by serving as a targeted drug delivery vehicle as well as an alternative to urine cytology.

Spinal Anesthesia Provides Longer Administration Time for Postoperative Intravesical Chemotherapy after TUR-B Operation.

PURPOSE: The aim of this study was to investigate the tolerability of postoperative early intravesical chemotherapy session after transurethral resection of the bladder tumor (TUR-B) according to the different anesthesia types. METHODS: The study was conducted between February 2017 and June 2020. Patients who were given intravesical mitomycin (MMC) 40 mg after TUR-B were included. Patients' risk categories (low, medium, and high) were determined according to the European Association of Urology (EAU) risk stratification system based on the tumor number, size (<3 and ≥3 cm), T stage (Ta and T1), and grade (low and high). Patients were divided into 2 groups according to the applied anesthesia technique as group S (spinal) and group G (general). The patients' visual analog scale (VAS) scores were recorded every 30 min for 2 h after urethral clamping. The patients' pain scores were recorded using the VAS questionnaire form at 30th (VAS1), 60th (VAS2), 90th (VAS3), and 120th (VAS4) min after the urethral clamping. Requirement of analgesic, urethral clamp removal time, total instillation time, and discharged urine volume were recorded. Complications and complication grade (1-5) were recorded according to the Clavien-Dindo system. RESULTS: A total of 232 consecutive patients who received intravesical MMC were included. Sociodemographic characteristics of group S (n = 113) and group G (n = 119) were similar (p < 0.05). There were no significant differences in tumor size, number of tumors, concomitant CIS, and T stage in both groups (p > 0.05). High-grade tumors were higher in group S (23.9 vs. 11%; p = 0.008). Requirement of analgesic (53.9 vs. 91.5%; p = 0.00) and termination of therapy <60' (2 vs. 26%; p = 0.00) and <120' (32.7 vs. 76.4%; p = 0.00) were significantly lower in group S. The mean instillation time (108.05 ± 19.40 vs. 85.67 ± 24.66 min; p = 0.00) was found significantly higher for group S. In group G, mean VAS1-4 scores were significantly higher than in group S (p < 0.05). Linear correlation analyses showed that the VAS score is correlated with the instillation time (p < 0.05). The rates of minor (I-III) (7 vs. 8%; p = 0.706) and major (IV-V) (0.9 vs. 1.6%; p = 0.590) complications were similar in both groups. CONCLUSION: The patients' tolerability of intravesical MMC treatment can be improved by spinal anesthesia. It provides longer instillation time and less pain during intravesical chemotherapy.

Effect of low-energy shock wave therapy on intravesical epirubicin delivery in a rat model of bladder cancer.

OBJECTIVES: To study the efficacy of low-energy shock wave therapy (LESW) on enhancing intravesical epirubicin (EPI) delivery in a rat model of bladder cancer (BCa). MATERIALS AND METHODS: A total of 100 female Fischer rats were randomly allocated into five groups: control; BCa; LESW; EPI; and EPI plus LESW. After BCa induction by N-butyl-N-(4-hydroxybutyl)nitrosamine, EPI (0.6 mg/0.3 mL of EPI diluted in 0.3 mL saline) or saline (0.6 mL) was administered and retained in the bladders for 1 h with or without LESW treatment (300 pulses at 0.12 mJ/mm2 ). This was repeated weekly for 6 weeks. Survival was then calculated, rats were weighed and their bladders were harvested for bladder/body ratio estimation, histopathological examination, p53 immunostaining, miR-210, hypoxia-inducible factor (HIF)-1α, tumour necrosis factor (TNF)-α and interleukin (IL)-6 relative gene expression and fluorescence spectrophotometric drug quantification. Heart and blood samples were also collected for assessment of the safety profile and toxicity. RESULTS: The EPI plus LESW group had significantly lower mortality rates, loss of body weight and bladder/body ratio. Histopathological results in terms of grossly visible bladder lesions, mucosal thickness, dysplasia formation and tumour invasion were significantly better in the combined treatment group. The EPI plus LESW group also had statistically significant lower expression levels of p53 , miR-210, HIF-1α, TNF-α and IL-6. LESW increased urothelial concentration of EPI by 5.7-fold (P < 0.001). No laboratory variable exceeded the reference ranges in any of the groups. There was an improvement of the indicators of EPI-induced cardiomyopathy in terms of congestion, hyalinization and microvesicular steatosis of cardiomyocytes (P = 0.068, 0.003 and 0.046, respectively) in the EPI plus LESW group. CONCLUSIONS: The combined use of intravesical EPI and LESW results in less BCa invasion and less dysplasia formation, as LESW increases urothelial permeability of EPI and enhances its delivery into tumour tissues, without subsequent toxicity.

Impact of enhanced optical techniques at time of transurethral resection of bladder tumour, with or without single immediate intravesical chemotherapy, on recurrence rate of non-muscle-invasive bladder cancer: a systematic review and network meta-analysis of randomized trials.

OBJECTIVE: To assess whether single immediate intravesical chemotherapy (SIIC) adds value to bladder tumour management in combination with novel optical techniques: enhanced transurethral resection of bladder tumour (TURBT). METHODS: A systematic search was performed using the PubMed and Web of Science databases in September 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) extension statement for network meta-analyses. Studies that compared recurrence rates among intervention groups (TURBT with photodynamic diagnosis [PDD] ± SIIC, narrow-band imaging [NBI] ± SIIC, or white-light cystoscopy [WLC] + SIIC) and a control group (TURBT with WLC alone) were included. We used the Bayesian approach in the network meta-analysis. RESULTS: Twenty-two studies (n = 4519) met our eligibility criteria. Out of six different interventions including three different optical techniques, compared to WLC alone, blue-light cystoscopy (BLC) plus SIIC (odds ratio [OR] 0.349, 95% credible interval [CrI] 0.196-0.601) and BLC alone (OR 0.668, 95% CrI 0.459-0.931) were associated with a significantly lower likelihood of 12-month recurrence rate. In the sensitivity analysis, out of eight different interventions compared to WLC alone, PDD by 5-aminolevulinic acid plus SIIC (OR 0.327, 95% CrI 0.159-0.646) and by hexaminolevulinic acid plus SIIC (OR 0.376, 95% CrI 0.172-0.783) were both associated with a significantly lower likelihood of 12-month recurrence rate. NBI with and without SIIC was not associated with a significantly lower likelihood of 12-month recurrence rate (OR 0.385, 95% CrI 0.105-1.29 and OR 0.653, 95% CrI 0.343-1.15). CONCLUSION: Blue-light cystoscopy during TURBT with concomitant SIIC seems to yield superior recurrence outcomes in patients with non-muscle-invasive bladder cancer. The use of PDD was able to reduce the 12-month recurrence rate; moreover, concomitant SIIC increased this risk benefit by a 32% additional reduction in odds ratio. Although using PDD could reduce the recurrence rate, SIIC remains necessary. Moreover, ranking analysis showed that both PDD and NBI, plus SIIC, were better than these techniques alone.

The HELENA study: Hexvix®-TURB vs. white-light TURB followed by intravesical adjuvant chemotherapy-a prospective randomized controlled open-label multicenter non-inferiority study.

PURPOSE: Photodynamic diagnosis and white-light TURB with adjuvant intravesical chemotherapy (ICT) is widely used in treatment of bladder cancer. This non-inferiority trial is designed to demonstrate non-inferiority regarding recurrence-free survival (RFS) of Hexvix® TURB followed by immediate instillation compared to white-light TURB with immediate instillation followed by maintenance ICT. METHODS: Between 07/2010 and 12/2016, 129 patients with EORTC intermediate risk non-muscle invasive bladder cancer treated with TURB were included in this multicentre phase III study. Patients were randomized and received either white-light TURB with immediate ICT followed by maintenance ICT (n = 62, 20 mg Mitomycin weekly for 6 weeks as induction phase, afterwards 20 mg/month for 6 months) or Hexvix® TURB with immediate ICT only (n = 67, 40 mg Mitomycin). Primary study endpoint was RFS after 12 months. Hexvix® TURB was counted as non-inferior to white light alone if the upper limit of the one-sided 95% confidence interval of hazard ratio was lower than 1.676. Due to the non-inferiority design, the per-protocol population was used as the primary analysis population (n = 113) RESULTS: Median follow-up was 1.81 years. Hexvix® group showed more events (recurrence or death) than white-light group (19 vs. 10) resulting in a HR of 1.29 (upper limit of one-sided 95%-CI = 2.45; pnon-inferiority = 0.249). The ITT population yielded similar results (HR = 1.67); 3.18], pnon-inferiority = 0.493). There was no significant difference in overall survival between both groups (p = 0.257). CONCLUSION: Non-inferiority of Hexvix® TURB relative to white-light TURB with maintenance Mitomycin instillation in intermediate risk urothelial carcinoma of the bladder was not proven. Hence a higher effect of maintenance ICT is to assume compared to a Hexvix®-improved TURB only, confirming its important role in patient treatment.

Treatment of Large Non-Muscle-Invasive Bladder Cancer: The Potential Role of Neoadjuvant Intravesical Chemotherapy.

INTRODUCTION: The endoscopic resection of large and bulky bladder cancers represents a challenge. To reduce the tumor and make it more easy to resect, we used neoadjuvant short and intensive intravesical mitomycin (MMC) therapy. METHODS: Patients with large bladder tumors were evaluated for this study. At cystoscopy, the surgeon evaluated the feasibility of complete resection. In patients where this was not possible, biopsies from the tumor, bladder mucosa, and prostatic urethra were taken. These patients then underwent a short and intensive cytoreductive schedule of intravesical MMC. This was then followed by TUR-BT. RESULTS: Fifteen patients were included in our study. The mean age was 74 years (range: 56-82; SD ±6 years). Mean tumor size was 51 mm (range: 35-65; SD ±8 mm). After neoadjuvant treatment, complete resection was then feasible in all patients. The mean tumor volume after the chemo-resection had reduced to 34 mm (range: 10-50; SD ±13 mm). No adverse effects were reported. CONCLUSION: Intravesical cytoreductive neoadjuvant MMC as an initial treatment of large NMIBC can be considered safe, effective, and feasible.

Safety and efficacy of intravesical chemotherapy and hyperthermia in the bladder: results of a porcine study.

BACKGROUND: Hyperthermia (heating to 43 °C) activates the innate immune system and improves bladder cancer chemosensitivity. OBJECTIVE: To evaluate the tissue penetration and safety of convective hyperthermia combined with intravesical mitomycin C (MMC) pharmacokinetics in live porcine bladder models using the Combat bladder recirculation system (BRS). METHODS: Forty 60 kg-female swine were anesthetized and catheterized with a 3-way, 16 F catheter. The Combat device was used to heat the bladders to a target temperature of 43 °C with recirculating intravesical MMC at doses of 40, 80, and 120 mg. Dwell-heat time varied from 30-180 min. Rapid necropsy with immediate flash freezing of tissues, blood and urine occurred. MMC concentrations were measured by liquid chromatography tandem-mass spectrometry. RESULTS: The Combat BRS system was able to achieve target range temperature (42-44 °C) in 12 mins, and this temperature was maintained as long as the device was running. Two factors increased tissue penetration of MMC in the bladder: drug concentration, and the presence of heat. In the hyperthermia arm, MMC penetration saturated at 80 mg, suggesting that with heating, drug absorption may saturate and not require higher doses to achieve the maximal biological effect. Convective hyperthermia did not increase the MMC concentration in the liver, heart, kidney, spleen, lung, and lymph node tissue even at the 120 mg dose. CONCLUSIONS: Convective bladder hyperthermia using the Combat BRS device is safe and the temperature can be maintained at 43 °C. Hyperthermia therapy may increase MMC penetration into the bladder wall but does not result in an increase of MMC levels in other organs.

Efficacy of intra-arterial chemotherapy combined with intravesical chemotherapy in T1G3 bladder cancer when compared with intravesical chemotherapy alone after bladder-sparing surgery: a retrospective study.

PURPOSE: To assess the efficacy of intra-arterial chemotherapy (IAC) combined with intravesical chemotherapy (IVC) in T1G3 bladder cancer (Bca) after transurethral resection of bladder tumor (TURBT). METHODS: Our study retrospectively reviewed 200 patients with T1G3 BCa who had all undergone TURBT. The patients' medical records were divided into two groups, one group only had IVC with pirarubicin after surgery, and the other group had IAC (cisplatin and epirubicin) combined with IVC after surgery. The patients were monitored regularly by urine cytology and cystoscopy. Survival and recurrence curves were calculated using the Kaplan-Meier method. Tumor recurrence, progression and tumor-specific death rate were compared with Chi-square test. A multivariate analysis was carried out to find out potential confounders. RESULTS: A total of 200 medical record was analyzed, 131 patients received IVC, 69 IAC + IVC treatment, tumor-specific death rate between the combined IAC and IVC compared to IVC alone was 7.25 and 17.6%, respectively (p < 0.05); the tumor recurrence rate between the two groups was 31.8% (22/69) and 44.3%, respectively (58/131) (p < 0.05), and tumor recurred later in the IAC + IVC group (p < 0.05), tumor progression rate was 18.8% (13/69) and 28.2% (37/131), respectively, with p < 0.05. Overall survival was longer in IAC + IVC group (p < 0.05). Using the multivariable regression model, IAC was significantly related to disease recurrence (p < 0.05) and overall survival (p < 0.05). CONCLUSION: T1G3 BCa post-TURBT surgery patients who underwent IAC combined with IVC had a longer overall survival and increased time interval to first recurrence, lower tumor recurrence rate, progression rate and tumor-specific death rate than compared with those who only underwent IVC alone.

Efficacy analysis of a novel thermochemotherapy scheme with pirarubicin for intermediate- and high-risk nonmuscle-invasive bladder cancer: a single-institution nonrandomized concurrent controlled trial.

Objective: To compare the efficacy and safety of a novel thermochemotherapy scheme and the instillation of pirarubicin (THP) without hyperthermia in patients with intermediate- and high-risk nonmuscle-invasive bladder cancer (NMIBC). Materials and methods: Between June 2012 and December 2016, 300 patients with urothelial carcinoma of the bladder undergoing intravesical adjuvant therapy with THP after transurethral resection of bladder tumors (TURBT) were enrolled in the study. These patients were divided into the CTHC group (thermochemotherapy composed of three consecutive sessions in which only the second hyperthermia was combined with THP, followed by intravesical instillation with THP without using hyperthermia) and the THP group (instillation of THP without hyperthermia). Cystoscopy and urinary cytology were repeated every 3 months. The primary endpoint was 24-month recurrence-free survival (RFS). Secondary endpoints included 24-month progression-free survival (PFS) and adverse event (AE) rates. Results: Baseline characteristics of the CTHC (n = 76) and THP (n = 85) groups were well-balanced. The 24-month RFS was 82.9% in the CTHC group and 63.5% in the THP group (log-rank p = .008). A significantly higher percentage of patients in the CTHC group achieved PFS than in the THP group (97.4% versus 87.1%; log-rank p = .011). There was no significant difference in AEs between the two groups (p > .05). Based on Cox proportional hazards models, CTHC was the only factor that contributed independently to improved RFS (hazard ratio, 0.422; 95% confidence interval, 0.214-0.835; p = .013). Conclusion: The CTHC scheme is a safe and effective adjuvant treatment option after TURBT for patients with intermediate- and high-risk NMIBC.