Edirne, Turkey

Low Energy Shock Wave Therapy and Non-Muscle Invasive Bladder Cancer

The investigators hypothesize that low energy shock wave therapy (LESW) might induce damage to the tumor tissues of non-muscle invasive bladder cancer (NMIBC), so they could be ablated and detached from the surface. The patients who are suffering from NMIBC will be randomly allocated into two groups: The first group (control group): 25 patients will be exposed to sham treatment before transurethral resection of bladder tumor (TURBT) without using LESW therapy. The second group (LESW group): 25 patients will be exposed to LESW therapy before TURBT. The shock wave applicator (Dornier AR2, shock wave device, Dornier MedTech 2010, Wessling, Germany) will be gently placed directly on the ultrasound transmission gel over the skin surface of the suprapubic region above the urinary bladder at the site of the papillary lesion (US guided) and at other five points. Points 1 and 2 will be at the level of transverse crease 2 cm above the pubic bone and 5 cm from each, points 3 and 4 will 2 cm above points 1 and 2, and point 5 will be centered of points 1-4. A total of 2000 pulses at 0.25 mJ/mm2 will be delivered with a frequency of 3 pulses per second. The position of the shock wave applicator will be changed after every 400 pulses. The apoptotic effect of LESW will be studied via histopathological examination for the type of bladder tumor, pathological stage, grade, association of carcinoma in situ and morphological features of apoptosis in terms of compaction of the nuclear chromatin (pyknosis), loss of cellular volume and chromatin condensation on the nuclear envelope (nuclear crescents), Immunohistochemical analysis of anti-caspase-3 antibody and molecular studies of Bax (an apoptotic promotor), BCL-2 and Survivin (apoptotic inhibitors) Relative Gene Expression in the resected bladder tissues. The patients will receive intravesical chemotherapy or BCG immunotherapy and they will be followed up at outpatient clinic for two years by MRI, outpatient cystoscopy and cytology to identify the recurrence and progression rate of NMIBC.

Immediate Chemotherapy Following Resection for High-Risk Non-Muscle-Invasive Bladder Cancer

Bladder cancer ranks as the ninth most prevalent cancer globally, with urothelial carcinoma being the primary form, leading to over 220,000 deaths annually. While 70-75% of bladder cancer cases initially present as non-muscle invasive bladder cancer (NMIBC) with favorable prognoses, the recurrence rate can reach 78% within five years post-standard treatment. The primary objective of transurethral resection of bladder tumors (TURBT) is to accurately diagnose and completely eliminate all visible lesions, as the quality of resection significantly impacts prognosis. However, a systematic review reveals a notable risk of residual tumor post-initial resection. For individuals with high-risk non-muscle invasive bladder cancer (NMIBC), EAU guidelines recommend a follow-up resection 2-6 weeks later. Clinical trials have demonstrated that administering a single chemotherapy session within 24 hours of the initial resection can lower recurrence rates. This approach may work by eradicating floating tumor cells, ablating residual tumor cells, and addressing overlooked small tumors. Gemcitabine and cisplatin (GC) have good efficacy and tolerance in patients with bladder cancer and have become the most commonly used regimen in the neoadjuvant treatment of bladder cancer. There is currently a lack of strong evidence that GC chemotherapy 24 hours after surgery can safely and effectively reduce the risk of recurrence in suspected high-risk NMIBC cases. Our goal is to conduct a prospective clinical trial to investigate the feasibility of this treatment method by evaluating the incidence of adverse events and recurrence-free survival in this group of patients by administering systemic chemotherapy 24 hours after TURBT for patients with suspected high-recurrence bladder cancer.

Enfortumab Vedotin and Pembrolizumab Combined With Radiotherapy in Muscle Invasive Bladder Cancer

PRIMARY OBJECTIVES: I. To determine the recommended phase II dose (RP2D) of enfortumab vedotin given in combination with pembrolizumab and concurrent radiation therapy (RT). (Phase Ib). II. To assess the toxicity and safety of enfortumab vedotin given in combination with pembrolizumab and concurrent radiation therapy (RT). (Phase Ib). III. To evaluate the rate of clinical complete response to treatment (cCR) at the RP2D based on 6-month post-treatment cystoscopy, TURBT, cytology, and cross sectional imaging. (Phase II). IV. To characterize the safety of enfortumab vedotin at the RP2D given in combination with pembrolizumab and concurrent radiation therapy (RT). (Phase II). SECONDARY OBJECTIVES: I. To evaluate the rate of cCR 6 months post-treatment start based on cystoscopy, TURBT, and cross sectional imaging. (Phase Ib) II. To evaluate the preliminary efficacy of enfortumab vedotin given in combination with pembrolizumab and concurrent radiation therapy (RT) as measured by 1-year recurrence free survival rate, 2-year cystectomy-free survival rate, 2-year overall survival rate, the median recurrence free survival (RFS) rate, median overall survival, and median cystectomy-free survival. (Phase Ib and Phase II) III. To assess the downstaging to ≤ pT1N0 pT1 or less following completion of treatment, based on 6-month post-treatment cystoscopy, for participants treated at RP2D of enfortumab vedotin (EV). (Phase Ib and Phase II) IV. To assess the downstaging to ≤ pT1N0 or less following completion of treatment, based on 6-month post-treatment cystoscopy, for participants across all EV dose levels. (Phase Ib and Phase II). EXPLORATORY OBJECTIVES: I. Assessment of change in tumor gene expression signatures using single-cell ribonucleic acid (RNA) sequencing (scRNA-Seq) following initiation of combination treatment. II. Assessment of the change in the populations of tumor-infiltrating immune cells (TIICs) induced by initiation of the combination treatment. III. Determination of the impact of EV/pembrolizumab combination treatment on programmed death-ligand 1 (PD-L1) expression in tumor cells and TIICs, as well as on other immunologic predictive markers. IV. Assessment of modulation of tumor microenvironment pre- and post-initiation of combination treatment using multiplex immunohistochemistry (IHC). V. Assessment of the modulation of circulating immune cells following initiation of combination treatment using mass cytometry (cytometry by time of flight, or CyTOF). VI. Assessment of the change in T-cell receptor repertoire by scRNA-Seq following initiation of combination treatment. VII. Change in tumor expression of nectin cell adhesion molecule 4 (Nectin-4) following combination treatment relative to baseline. VIII. Assessment in the change in CD3+ T cell density (T cell count/μm^2) from baseline biopsy to post-RT biopsy in participants with residual tumor, across all EV dose levels and at RP2D. OUTLINE: This is a phase Ib, dose escalation study of enfortumab vedotin followed by a phase II study. Participants receive enfortumab vedotin and pembrolizumab for up to 5 cycle of enfortumab vedotin and up to 17 cycles of pembrolizumab in the absence of disease progression or unacceptable toxicity. Beginning on cycle 1 day 1, participants also undergo non-investigational, standard of care intensity modulated radiation therapy (IMRT) over 6.5-8 weeks. After completion of study treatment, participants are followed up at 90 days and then every 12 weeks for up to 5 years.

Cadonilimab Plus Nab-Paclitaxel for Recurrent or Metastatic Muscle Invasive Bladder Cancer

Cadonilimab(AK104) is a first-in-class bispecific, humanized IgG1 antibody targeting PD-1 and CTLA-4, which has the potential to boost immune surveillance in tumors. The goal of this clinical phase II trial is to evaluate the efficacy and safety of AK104 combined with Nab-Paclitaxel as first line therapy for recurrent or metastatic muscle invasive bladder.

A Bladder-Sparing Treatment Strategies of Large-Volume Non-Muscle-Invasive Bladder Cancer

A Trial of Durvalumab (MEDI4736) Plus Monalizumab in Non-Muscle-Invasive Bladder Cancer

Bladder Preservation for Patients with Muscle Invasive Bladder Cancer (MIBC) with Variant Histology

Trimodal therapy (TMT) is accepted as an NCCN category 1 alternative to radical cystectomy (with neoadjuvant chemotherapy) in patients with cT2N0M0 muscle-invasive urothelial cell bladder cancer (MIBC). Not all patients with MIBC have pure urothelial cell carcinoma; urothelial carcinoma with variant histology (VH) described any morphologic variant of conventional urothelial carcinoma that is believed to be derived from urothelial carcinoma and is typically admixed with conventional urothelial carcinoma in the same tumor. Variant histologies described include squamous differentiation, glandular differentiation, micropapillary, sarcomatoid, small cell/neuroendocrine, plasmacytoid and nested variant. This is a rare tumor type and understudied. For patients with variant histologies there is limited data on the use of trimodal therapy. There are a couple single institution retrospective studies and data from the NCDB, but no prospective data.

Enfortumab Vedotin and Stereotactic Radiation for Localized, Cisplatin Ineligible Muscle Invasive Bladder Cancer

STAR EV is a phase I/II trial with safety lead in, designed to assess safety and preliminary efficacy signal in improving pathologic complete response by adding stereotactic radiation to neoadjuvant enfortumab vedotin. Participants will be adult patients with urothelial predominant bladder cancer ineligible for neoadjuvant cisplatin-based therapy (based on provider assessment) and planned for radical cystectomy. All participants will undergo the same treatment: - Enfortumab vedotin (PADCEV) 1.25mg/kg (max 125mg) IV Day 1, 8 q21 day cycle x 3 cycles - Radiation: Stereotactic radiotherapy to bladder (partial bladder volume preferred) 5 fractions; either sequential to EV treatment or concurrent with EV treatment - Surgery: Standard of care radical cystectomy and pelvic lymph node dissection with urinary diversion per surgeon discretion. The study will use a patient safety lead-in incorporating escalation of EV-RT from sequential to concurrent use with pre-defined stopping rules according to treatment-related adverse event (TRAE) rate of grade 3 or above. Primary endpoints are related to safety (maximum tolerated dose "regimen" based on dose limiting toxicities (DLTs) observed) and pathologic complete response rate at the time of surgery. Subjects will be followed for one year following cystectomy, or completion of neoadjuvant therapy for any subject who does not undergo cystectomy for any reason.

mpMRI Compared to Diagnostic TURBT in Patients With Suspected Muscle-Invasive Bladder Cancer

The Prognostic Impact of Tumor Location in Non-Muscle-Invasive Bladder Cancer Patients

Background Most bladder cancers are non-muscle invasive bladder cancer (NMIBC), and transurethral resection of bladder tumors (TURBT) is the standard treatment. However, postoperative recurrence poses a challenge, and the influence of bladder tumor location on prognosis is unclear. This study aims to investigate how tumor location affects NMIBC patients' prognosis undergoing TURBT, and seeks optimal surgical approaches. Methods Conducted a multicenter study, including Chinese NMIBC data from 15 hospitals (1996-2019) and SEER 17 registries (2000-2020). Analyzed patients initially diagnosed with NMIBC undergoing TURBT or partial cystectomy, excluding cases with lost follow-up or missing data. Studied overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS). Employed Kaplan-Meier, Cox regression, and propensity score matching to explore the association between tumor location and prognosis. Stratified populations were analyzed to minimize bias. Findings This study, involving 118,477 NMIBC patients, highlighted tumor location as a crucial factor impacting post-TURBT prognosis. Anterior wall and dome tumors independently predicted adverse outcomes in both cohorts. For anterior wall tumors, Chinese cohort showed OS HR 4.35, p < 0.0001; RFS HR 2.21, p < 0.0001; SEER OS HR 1.10, p = 0.0001; DSS HR 1.13, p = 0.0183. Dome tumors displayed similar trends (Chinese NMIBC cohort OS HR 7.91, p < 0.0001; RFS HR 2.12, p < 0.0001; SEER OS HR 1.05, p = 0.0087; DSS HR 1.14, p = 0.0006). Partial cystectomy significantly improved dome tumor survival compared to standard TURBT (p < 0.01). Interpretation This study reveal that NMIBC tumor location significantly influences TURBT treatment outcomes. Specifically, tumors in the anterior wall and bladder dome have worse post-TURBT prognosis. Compared to TURBT, partial cystectomy improves prognosis for bladder dome tumors. This study guides personalized treatment and prognosis management for NMIBC patients.