BACKGROUND: High grade, non-muscle invasive bladder cancer (NMIBC) is usually treated with intravesical Bacillus Calmette-Guérin. Chemohyperthermia therapy (CHT) may be a novel alternative therapy for the treatment of NMIBC.
OBJECTIVE: To evaluate the recurrence-free survival (RFS) of patients treated with CHT using the Combat bladder recirculation system (BRS) for NMIBC.
METHODS: This was a prospective multi-institutional study of 1,028 consecutive patients with NMIBC undergoing CHT between 2012 and 2020. A total of 835 patients were treated with CHT with Mitomycin C (MMC). Disease was confirmed on transurethral resection of bladder tumor (TURBT) prior to starting CHT. Follow-up included cystoscopy and subsequent TURBT if recurrence/progression was suspected. The primary endpoint was RFS. Secondary endpoints were progression-free survival (PFS) and adverse events from CHT.
CONCLUSIONS: Median follow up was 22.4 months (Interquartile range (IQR): 12.8 -35.8). Median age was 70.4 years (IQR: 62.1 -78.6). A total of 557 (66.7%), 172 (20.6) and 74 (8.9%) of patients were classified to BCG naïve, BCG unresponsive and BCG failure, respectively. The RFS at 12 months and 24 months for BCG naïve was 87.6% (95% CI 85.0% - 90.4%) and 75.0% (95% CI 71.3% - 78.8%), respectively. The RFS at 12 months and 24 months for BCG unresponsive cohort was 78.1% (95% CI 72.0% - 84.7%) and 57.4% (95% CI 49.7% - 66.3%), respectively. The RFS at 24 months for the BCG unresponsive cohort for CIS with/without papillary disease and papillary only disease were 43.6% (95% CI 31.4% -60.4%) and 64.5% (95% CI 55.4% - 75.1%), respectively. Minor adverse events occurred in 216 (25.6%) patients and severe events occurred in 17 (2.0%) patients.
CONCLUSIONS: CHT with MMC using the Combat BRS is effective in the medium term and has a favorable adverse event profile.

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.
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.
CONCLUSIONS: Switching IVC agents does not improve RFS and PFS for patients with short-term recurrent high-risk NMIBC.

OBJECTIVE: 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.
CONCLUSIONS: 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.

Adjuvant intravesical chemotherapy following tumour resection is recommended for intermediate-risk non-muscle-invasive bladder cancer (NMIBC).
To assess the efficacy and safety of adjuvant intravesical chemohyperthermia (CHT) for intermediate-risk NMIBC.
HIVEC-II is an open-label, phase 2 randomised controlled trial of CHT versus chemotherapy alone in patients with intermediate-risk NMIBC recruited at 15 centres between May 2014 and December 2017 (ISRCTN 23639415). Randomisation was stratified by treating hospital.
Patients were randomly assigned (1:1) to adjuvant CHT with mitomycin C at 43°C or to room-temperature mitomycin C (control). Both treatment arms received six weekly instillations of 40 mg of mitomycin C lasting for 60 min.
The primary endpoint was 24-mo disease-free survival as determined via cystoscopy and urinary cytology. Analysis was by intention to treat.
A total of 259 patients (131 CHT vs 128 control) were randomised. At 24 mo, 42 patients (32%) in the CHT group and 49 (38%) in the control group had experienced recurrence. Disease-free survival at 24 mo was 61% (95% confidence interval [CI] 51-69%) in the CHT arm and 60% (95% CI 50-68%) in the control arm (hazard ratio [HR] 0.92, 95% CI 0.62-1.37; log-rank p = 0.8). Progression-free survival was higher in the control arm (HR 3.44, 95% CI 1.09-10.82; log-rank p = 0.02) on intention-to-treat analysis but was not significantly higher on per-protocol analysis (HR 2.87, 95% CI 0.83-9.98; log-rank p = 0.06). Overall survival was similar (HR 2.55, 95% CI 0.77-8.40; log-rank p = 0.09). Patients undergoing CHT were less likely to complete their treatment (n =75, 59% vs n = 111, 89%). Adverse events were reported by 164 patients (87 CHT vs 77 control). Major (grade III) adverse events were rare (13 CHT vs 7 control).
CHT cannot be recommended over chemotherapy alone for intermediate-risk NMIBC. Adverse events following CHT were of low grade and short-lived, although patients were less likely to complete their treatment.
The HIVEC-II trial investigated the role of heated chemotherapy instillations in the bladder for treatment of intermediate-risk non-muscle-invasive bladder cancer. We found no cancer control benefit from heated chemotherapy instillations over room-temperature chemotherapy. Adverse events following heated chemotherapy were low grade and short-lived, although these patients were less likely to complete their treatment.

Intravesical chemotherapy after transurethral resection is a treatment option in patients with non-muscle invasive bladder cancer. The efficacy of intravesical chemotherapy is determined by the cellular uptake of intravesical drugs. Therefore, drug delivery technologies in the urinary bladder are promising tools for enhancing the efficacy of intravesical chemotherapy. Ultrasound-triggered microbubble cavitation may enhance the permeability of the urothelium, and thus may have potential as a drug delivery technology in the urinary bladder. Meanwhile, the enhanced permeability may increase systemic absorption of intravesical drugs, which may increase the adverse effects of the drug. The aim of this preliminary safety study was to assess the systemic absorption of an intravesical drug that was delivered by ultrasound-triggered microbubble cavitation in the urinary bladder of normal dogs. Pirarubicin, a derivative of doxorubicin, and an ultrasound contrast agent (Sonazoid) microbubbles were administered in the urinary bladder. Ultrasound (transmitting frequency 5 MHz; pulse duration 0.44 μsec; pulse repetition frequency 7.7 kHz; peak negative pressure -1.2 MPa) was exposed to the bladder using a diagnostic ultrasound probe (PLT-704SBT). The combination of ultrasound and microbubbles did not increase the plasma concentration of intravesical pirarubicin. In addition, hematoxylin and eosin staining showed that the combination of ultrasound and microbubble did not cause observable damages to the urothelium. Tissue pirarubicin concentration in the sonicated region was higher than that of the non-sonicated region in two of three dogs. The results of this pilot study demonstrate the safety of the combination of intravesical pirarubicin and ultrasound-triggered microbubble cavitation, that is, ultrasound-assisted intravesical chemotherapy.

BACKGROUND: Bladder cancer imposes a significant public health burden on the European Union. There is a need for cost-effective treatment and follow-up regimens.
OBJECTIVE: To assess the cost-effectiveness of immediate mitomycin C (MMC) instillation within 1 d after surgery compared to delayed MMC instillation within 2 wk after surgery with further adjuvant treatment, depending on the patient\'s risk group.
METHODS: This economic evaluation was based on a randomized controlled trial among 2243 Dutch patients with non-muscle-invasive bladder cancer (NMIBC) patients from a health care perspective over a 3-yr time period.
METHODS: The treatment effect was measured as time to recurrence and recurrence-free survival. Missing effect data were imputed with multiple imputation. Health care utilization and related costs were estimated on the basis of treatment protocols for NMIBC patients in the Netherlands. Statistical uncertainty was estimated using bootstrapping and is graphically presented using cost-effectiveness planes and cost-effectiveness acceptability curves.
CONCLUSIONS: Time to recurrence was significantly longer for immediate MMC instillation (27.31 mo) than for delayed MMC instillation (24.97 mo), with an adjusted mean difference of 2.21 mo (95% confidence interval [CI] 1.58-2.84). The proportion of patients with recurrence-free survival was significantly higher after immediate MMC instillation (0.65) than after delayed MMC instillation (0.56), with an adjusted mean difference of 0.08 (95% CI 0.06-0.11). Total mean health care costs per patient were significantly lower for immediate MMC instillation (€22 959) than for delayed MMC instillation (€24 624), with an adjusted mean difference of -€1350 (95% CI -€1799 to -€900). The study is limited by the retrospective estimation of costs.
CONCLUSIONS: This trial-based cost-effectiveness analysis shows that from a health care perspective, immediate MMC instillation is more effective and less expensive compared to delayed MMC instillation.
RESULTS: We assessed the cost-effectiveness of immediate bladder instillation of mitomycin C after surgery to reduce the risk of recurrence after removal of the bladder tumor as compared to delayed instillation in a large Dutch population of patients with non-muscle-invasive bladder cancer. We found that immediate instillation was more effective and less expensive than delayed instillation. We conclude that immediate mitomycin C instillation is a cost-effective treatment for non-muscle-invasive bladder cancer.

OBJECTIVE: Although an immediate postoperative instillation of chemotherapy (IPOIC) after transurethral resection of bladder tumors (TURBT) is recommended for the prevention of recurrences of non-muscleinvasive bladder cancer (NMIBC), evidence shows there is an important compliance failure worldwide. We believe that an immediate neoadjuvant instillation of chemotherapy (INAIC) can act similarly, reducing the recurrence risk of NMIBC. Here we present the interim analysis of the PRECAVE clinical trial.
METHODS: Patients with clinically diagnosed NMIBC were randomized to receive an INAIC with mitomycin C before TURBT (Group A) or to a control group with TURBT only (Group B). Primary end point was to compare the efficacy of an INAIC in the early recurrence-free survival (RFS). Secondary end points were: RFS in patients who did not receive adjuvant treatments, toxicity, and feasibility.
RESULTS: A total of 124 patients with Ta/T1 G1-G3NMIBC were included in the initial analysis (Group A:64, Group B: 60). Demographics, risk classification, complications, and adjuvant treatments were balanced between groups. Eighty-four patients (Group A: 45, Group B: 39) who completed a one-year follow-up were included in the efficacy analysis and no difference was observed in the RFS between groups (p=0.3). In the subgroup of patients who did not receive adjuvant treatments, we found a significant difference in favor of an INAIC (p=0.009) and an 80% reduction in the risk of early recurrences (Hazard Ratio: 0.20; 95% confidence interval: 0.05-0.81; p=0.0024). No differences were observed in adverse events. Only 4 patients did not receive an INAIC despite being planned.
CONCLUSIONS: In this interim analysis, although we could not demonstrate a reduction in the RFS of all patients, we did find a significant decrease of recurrences in patients who did not receive adjuvant treatments. The administration of an INAIC seems to be safe and our protocol appears feasible and reproductive.
UNASSIGNED: Aunque el uso de una instilación postoperatoria inmediata de quimioterapia (IPOIQ) tras una resección transuretral vesical (RTUV) esta recomendada para prevenir recurrencias de carcinoma vesical no músculo invasivo (CVNMI), no se llega a realizar en muchos casos debido a fallos en su cumplimiento. Nosotros creemos que una instilación neoadyuvante inmediata de quimioterapia (INAIQ) puede actuar de manera similar reduciendo el riesgo de recurrencias. Presentamos el análisis intermedio del ensayo clínico PRECAVE.MATERIAL Y MÉTODOS: Se aleatorizó a pacientes diagnosticados de CVNMI a recibir una INAIQ con mitomicina C antes de la RTUV (Grupo A) o a un grupo control con RTUV solamente (Grupo B). El objetivo primario fue comparar la eficacia de una INAIQ en la supervivencia libre de recurrencia (SLR) temprana. Los objetivos secundarios fueron la SLR en pacientes que no recibieron tratamientos adyuvantes, toxicidad y viabilidad.
UNASSIGNED: Analizamos un total de 124 pacientes con CVNMI Ta/T1G1-G3 fueron analizados (Grupo A:64, Grupo B: 60). No se encontraron diferencias entre datos demográficos, grupos de riesgo, complicaciones o tratamientos adyuvantes. Para el análisis de eficacias e incluyeron 84 pacientes (Grupo A: 45, Grupo B:39) con al menos un año de seguimiento, sin observar diferencias en la SLR (p=0,3). Sin embargo, en el subgrupo que no recibió tratamientos adyuvantes, sí encontramos una diferencia significativa a favor de la INAIQ (p=0,009), y una reducción del riesgo de recurrencias tempranas del 80% (Hazard Ratio: 0,20; intervalo de confianza 95%: 0,05-0,81; p=0,0024). No se observaron diferencias en la aparición de eventos adversos. Solo 4 pacientes no recibieron un INAIC a pesar de estar planificado.
UNASSIGNED: En este análisis intermedio, aunque no pudimos demostrar una reducción en la SLR de todos los pacientes, sí encontramos una diferencia en el subgrupo que no recibió tratamientos adyuvantes. La administración de una INAIC parece ser segura, y nuestro protocolo parece factible y reproducible.

UNASSIGNED: Due to the poor prognosis, the treatment of high-risk bladder cancer (HRBC) remains controversial. This meta-analysis aims to access the efficacy of intra-arterial chemotherapy (IAC) combined with intravesical chemotherapy (IC) versus IC alone after bladder-sparing surgery in HRBC.
UNASSIGNED: A systematic search of PubMed, Cochrane Library databases, EMBASE (until June 2020) was conducted. PRISMA checklist was followed. The data were analyzed by RevMan v5.3.0.
UNASSIGNED: A total of five articles including 843 patients were studied. The analysis demonstrated that the IAC + IC group had a greater improvement of overall survival (P = 0.02) and significant reduction in terms of tumor recurrence rate (P = 0.0006) and tumor progression rate (P = 0.008) compared with the IC group. The recurrence-free survival in the IAC + IC group was significantly higher than that in the IC group (P = 0.004), but there was no significant difference in progression-free survival between the two groups (P = 0.32). In addition, the combination of IAC and IC significantly extended tumor recurrence interval (P = 0.0001) and reduced tumor-specific death rate (P = 0.01) for patients with HRBC compared with IC alone. For side effects related with IAC, although about half of the patients experienced some toxicities, most of them were mild and reversible (grades 1-2, 22.3% vs. grade 3-4, 2.7%), mainly including nausea/vomiting (P = 0.0001), neutropenia (P = 0.002), and alanine aminotransferase (P = 0.0001).
UNASSIGNED: Patients with HRBC treated with IAC + IC after bladder-sparing surgery had a marked improvement in the overall survival, recurrence-free survival, time interval to first recurrence, tumor recurrence rate, tumor progression rate, and tumor-specific death rate than patients treated with IC alone. However, progression-free survival was not significantly correlated with treatment strategy. In addition, patients seemed to tolerate well the toxicities related with IAC.
UNASSIGNED: PROSPERO, identifier CRD42021232679.

OBJECTIVE: 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).
CONCLUSIONS: 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.

To compare the efficacy and safety of hyperthermic intravesical chemotherapy (HIVEC) and intravesical chemotherapy (IVEC) in patients with intermediate and high risk nonmuscle-invasive bladder cancer (NMIBC) after transurethral resection.
We included 560 patients diagnosed with primary or recurrent NMIBC between April 2009 and December 2015 at 1 of 6 tertiary centers. We matched 364 intermediate or high risk cases and divided them into 2 groups: the HIVEC+IVEC group [chemohyperthermia (CHT) composed of 3 consecutive sessions followed by intravesical instillation without hyperthermia] and the IVEC group (intravesical instillation without hyperthermia). The data were recorded in the database. The primary endpoint was 2-year recurrence-free survival (RFS) in all NMIBC patients (n = 364), whereas the secondary endpoints were the assessment of radical cystectomy (RC) and 5-year overall survival (OS).
There was a significant difference in the 2-year RFS between the two groups in all patients (n = 364; HIVEC+IVEC: 82.42% vs. IVEC: 74.18%, P = 0.038). Compared with the IVEC group, the HIVEC+IVEC group had a lower incidence of RC (P = 0.0274). However, the 5-year OS was the same between the 2 groups (P = 0.1434). Adverse events (AEs) occurred in 32.7% of all patients, but none of the events was serious (grades 3-4). No difference in the incidence or severity of AEs between each treatment modality was observed.
This retrospective study showed that HIVEC+IVEC had a higher 2-year RFS and a lower incidence of RC than IVEC therapy in intermediate and high risk NMIBC patients. Both treatments were well-tolerated in a similar manner.