Induction and maintenance of sequential intravesical gemcitabine/docetaxel for intermediate and high-risk non-muscle invasive bladder cancer with different dosage protocols.

INTRODUCTION: The combination of sequential intravesical gemcitabine and docetaxel (Gem/Doce) chemotherapy has been considered a feasible option for BCG (Bacillus Calmette-Guérin) treatment in non-muscle invasive bladder cancer (NMIBC), gaining popularity during BCG shortage period. We seek to determine the efficacy of the treatment by comparing Gem/Doce induction alone vs induction with maintenance, and to evaluate the treatment outcomes of two different dosage protocols. METHODS: A bi-center retrospective analysis of consecutive patients treated with Gem/Doce for NMIBC between 2018 and 2023 was performed. Baseline characteristics, risk group stratification (AUA 2020 guidelines), pathological, and surveillance reports were collected. Kaplan-Meier survival analysis was performed to detect Recurrence-free survival (RFS). RESULTS: Overall, 83 patients (68 males, 15 females) with a median age of 73 (IQR 66-79), and a median follow-up time of 18 months (IQR 9-25), were included. Forty-one had an intermediate-risk disease (49%) and 42 had a high-risk disease (51%). Thirty-seven patients (45%) had a recurrence; 19 (23%) had a high-grade recurrence. RFS of Gem/Doce induction-only vs induction + maintenance was at 6 months 88% vs 100%, at 12 months 71% vs 97%, at 18 months 57% vs 91%, and at 24 months 31% vs 87%, respectively (log-rank, p < 0.0001). Patients who received 2 g Gemcitabine with Docetaxel had better RFS for all-grade recurrences (log-rank, p = 0.017). However, no difference was found for high-grade recurrences. CONCLUSION: Gem/Doce induction with maintenance resulted in significantly better RFS than induction-only. Combining 2 g gemcitabine with docetaxel resulted in better RFS for all-grade but not for high-grade recurrences. Further prospective trials are necessary to validate our results.

A systematic review of the efficacy of intravesical electromotive drug administration therapy for non-muscle invasive bladder cancer.

BACKGROUND: Non-muscle invasive bladder cancer (NMIBC) is characterized by a high rate of recurrence and progression, despite surgery and adjuvant therapies. OBJECTIVE: To analyze the published results on the effectiveness of mitomycin C (MMC) applied with an electromotive drug administration device (EMDA) in the treatment of patients with non-muscle invasive bladder tumors. METHOD: A systematic review was conducted using the PubMed and Google Scholar search platforms. We selected the studies that included the recurrence and/or progression rates or complete response rate in patients diagnosed with NMIBC according to their treatment and included MMC applied with EMDA. The last search was performed in November 2021. RESULTS: The search yielded 64 articles; 11 articles met the selection criteria. In two of the 11 selected articles, mitomycin C was applied with an EMDA device (MMC-EMDA) as an ablative treatment, avoiding surgery in 50% of the patients. In 1 of the 11 studies, the application of MMC-EMDA was used as an induction treatment using a single preoperative instillation with promising results. In the remaining 8 studies, adjuvant MMC was applied with the EMDA device; in 3 of these 8 cases, treatment with MMC-EMDA alone was applied initially. In another3 cases the same treatment was applied after nonresponse to bacillus Calmette Guerin (BCG), and in the last 2 studies, MMC-EMDA was applied in combination with the classic therapy (BCG). All the studies selected supported the efficacy and safety of MMC-EMDA in patients with intermediate and high- risk bladder cancer. In 3 studies, adjuvant therapy with MMC-EMDA was performed in nonresponders to BCG, finding that adjuvant therapy with MMC-EMDA applied to BCG nonresponders without CIS avoided or delayed surgery. CONCLUSIONS: The application of EMDA-enhanced MMC has been studied at different times of disease and with different administration protocols. It appears to delay bladder tumor recurrence and progression in certain populations. However, the methodological limitations of the published studies prevent definitive conclusions about its efficacy.

The efficacy of BCG TICE and BCG Connaught in a cohort of 2,099 patients with T1G3 non-muscle-invasive bladder cancer.

BACKGROUND: Potential differences in efficacy of different bacillus Calmette-Guérin (BCG) strains are of importance for daily practice, especially in the era of BCG shortage. OBJECTIVE: To retrospectively compare the outcome with BCG Connaught and BCG TICE in a large study cohort of pT1 high-grade non-muscle-invasive bladder cancer patients. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data were collected for 2,451 patients with primary T1G3 tumors from 23 centers who were treated with BCG for the first time between 1990 and 2011. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Using Cox multivariable regression and adjusting for the most important prognostic factors in this nonrandomized comparison, BCG Connaught and TICE were compared for time to recurrence, progression, and the duration of cancer specific survival and overall survival. RESULTS AND LIMITATIONS: Information on the BCG strain was available for 2,099 patients: 957 on Connaught and 1,142 on TICE. Overall, 765 (36%) patients received some form of maintenance BCG, 560 (59%) on Connaught and 205 (18%) on TICE. Without maintenance, Connaught was more effective than TICE only for the time to first recurrence (hazard ratio [HR] = 1.48; 95% CI: 1.20-1.82; P<0.001). With maintenance, TICE was more effective than Connaught for the time to first recurrence (HR = 0.66; 95% CI: 0.47-0.93; P = 0.019) with a trend for cancer specific survival (HR = 0.36; 95% CI: 0.14-0.92; P = 0.033). For time to progression and overall survival, Connaught and TICE had a similar efficacy. Compared to no maintenance therapy, maintenance BCG significantly reduced the risk of recurrence, progression and death, both overall, and disease specific, for TICE, but not for Connaught. CONCLUSIONS: We found that BCG Connaught results in a lower recurrence rate as compared with BCG TICE when no maintenance is used. However, the opposite is true when maintenance is given. PATIENT SUMMARY: As there is currently a BCG shortage, information on the efficacy of different BCG strains is important. In this nonrandomized retrospective comparison in over 2,000 patients, we found that BCG Connaught reduces the recurrence rate compared to BCG TICE when no maintenance is used, but the opposite is true when maintenance is given.

Single-center experience with botulinum toxin endoscopic detrusor injection for the treatment of congenital neuropathic bladder in children: effect of dose adjustment, multiple injections, and avoidance of reconstructive procedures.

OBJECTIVE: Since 2007, intra-detrusor OnabotulinumtoxinA (OnabotA) injections have been selectively offered at our institution for cases in which maximal anticholinergic therapy failed or was not tolerated. Herein we present our experience with this approach. MATERIALS AND METHODS: We prospectively obtained data on 17 patients who underwent OnabotA injections over a 4-year period. Demographic information, number of injections, and dose delivered were captured. Children were monitored with baseline and post-injection renal ultrasound, urodynamics, and assessed for side effects, satisfaction, and symptom improvement. RESULTS: Forty-three sessions were performed with injections given every ∼ 6 months. Mean patient age was 10.7 years (range, 3-17). Compared with baseline, after the first injection, mean bladder capacity adjusted for age and compliance improved by 27% (p = 0.039) and 45.2% (p = 0.041), respectively. After subsequent injections, these values increased to 35.7% (p = 0.043) and 55.1% (p = 0.091), respectively. Out of 13 symptomatic patients, ≥ 50% improvement was reported in ten (76.9%) and complete resolution in seven (53.8%). However, all three patients in whom the maximum dose of OnabotA was reduced from 300 to 200 units complained of recurrent symptoms. Fourteen children avoided surgical reconstruction as a second line of treatment. Overall patient/parental reported satisfaction rate was 70.6% (12/17). CONCLUSIONS: Intra-detrusor OnabotA injection is a promising intervention for management of neuropathic bladder in selected patients. Our data demonstrate improvement in symptoms and urodynamic parameters. Although an optimal dose has not been determined for children, we found optimal response with a maximum administration of OnabotA up to 300 units.

Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy.

BACKGROUND: Whether the commonly used bacillus Calmette-Guérin (BCG) strains Connaught and Tice confer different treatment responses in non-muscle-invasive bladder cancer (NMIBC) is unknown. OBJECTIVES: To compare clinical efficacy, immunogenicity, and genetics of BCG Connaught and Tice. DESIGN, SETTING, AND PARTICIPANTS: A prospective randomized single-institution trial with treatment of 142 high-risk NMIBC patients with BCG Connaught or Tice. INTERVENTION: Patients were randomized to receive six instillations of BCG Connaught or Tice. For experimental studies, BCG strains were compared in C57Bl/6 mice. Bladders and lymphoid tissues were analyzed by cytometry and the latter cultivated to detect live BCG. BCG genomic DNA was sequenced and compared with reference genomes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Recurrence-free survival was the primary end point of the clinical study. The Kaplan-Meier estimator was used for estimating survival and time-to-event end points. Nonparametric tests served for the analysis of the in vivo results. RESULTS AND LIMITATIONS: Treatment with BCG Connaught conferred significantly greater 5-yr recurrence-free survival compared with treatment with BCG Tice (p=0.0108). Comparable numbers of patients experienced BCG therapy-related side effects in each treatment group (p=0.09). In mice, BCG Connaught induced stronger T-helper cell 1-biased responses, greater priming of BCG-specific CD8(+) T cells, and more robust T-cell recruitment to the bladder than BCG Tice. Genome sequencing of the BCG strains revealed candidate genes potentially involved in the differential clinical responses. CONCLUSIONS: BCG strain may have an impact on treatment outcome in NMIBC immunotherapy. PATIENT SUMMARY: We compared the efficacy of two commonly used bacillus Calmette-Guérin (BCG) strains for the treatment of NMIBC and found that treatment with BCG Connaught prevented recurrences more efficiently than BCG Tice. Comparison of the immunogenicity of the two strains in mice indicated superior immunogenicity of BCG Connaught. We also identified genetic differences that may explain the differential efficacy of the Connaught and Tice BCG strains. TRIAL REGISTRATION: NCT00003779.