Investigation Into the Integration of Intracavitary Cryoablation and Immunotherapy in Bladder-Preserving Therapy

Professional Translation: This study is a single-center, prospective, non-randomized, parallel-controlled clinical trial initiated and conducted by the Department of Urology at the First Affiliated Hospital of Naval Medical University. The Principal Investigator is Professor Zhang Zhensheng, and the projected execution period for the project is from July 2025 to July 2027. The study aims to evaluate the efficacy and safety of an innovative integrated bladder-preserving treatment model-novel endoluminal precise cryoablation combined with Transurethral Resection of Bladder Tumor (TURBT), immunotherapy, and metronomic chemotherapy (the TECIC model)-in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). Bladder cancer is a common malignant tumor of the urinary system. While radical cystectomy remains the standard therapy, it is associated with significant trauma, numerous complications, and substantially impacts patient quality of life. Existing bladder-preservation strategies, such as TURBT alone or trimodal therapy (chemoradiation), face challenges including high recurrence rates and variable efficacy. This research builds upon prior development and clinical exploration of a domestically developed novel endoluminal liquid nitrogen balloon cryoablation technology. This technology enables precise cryoablation of the tumor base under direct endoscopic vision, inducing immunogenic cell death, which theoretically can synergize with immunotherapy and chemotherapy, offering a new approach to bladder-preserving treatment. The study plans to enroll 180 patients diagnosed with high-risk NMIBC via biopsy or TURBT. Patient preference will be a key factor in group assignment. The experimental group (n=90) will undergo TURBT combined with intraoperative endoluminal precise cryoablation (at least 2 freeze-thaw cycles per lesion, each cycle lasting 3-5 minutes), followed by adjuvant anti-PD-1 monoclonal antibody immunotherapy (e.g., Camrelizumab, Tislelizumab, etc., for at least 3-6 cycles) and metronomic chemotherapy with a Gemcitabine plus Cisplatin (GC) regimen (at least 4-6 cycles). The control group (n=90) will receive radical cystectomy and urinary diversion selected according to current guidelines and individual circumstances; postoperative adjuvant therapy will be at the discretion of the attending physician. The primary efficacy endpoint of the study is 5-year Overall Survival (OS). Secondary efficacy endpoints include the rate of local intravesical recurrence/progression, 1-year and 2-year OS, 1-year, 2-year, and 5-year Progression-Free Survival (PFS), as well as quality of life scores. The safety endpoint is the incidence of postoperative adverse events. Furthermore, the study will explore biomarkers such as changes in local immune infiltration (assessed by detecting multiple immune markers in biopsy tissue) and peripheral blood cytokine levels and immune cell function before and after treatment. Statistical analysis will employ the Full Analysis Set (FAS), the Per Protocol Set (PPS), and a 1:1 propensity score matching analysis set to reduce selection bias. Analysis of the primary efficacy index will be conducted at a one-sided significance level of 0.025. In contrast, other indexes will use a two-sided significance level of 0.05, utilizing SAS 9.3 statistical software. Descriptive analysis, efficacy analysis, and safety analysis will be performed separately. This study will strictly adhere to the principles of the Declaration of Helsinki, relevant Chinese regulations, and Good Clinical Practice (GCP). The protocol has been submitted for review and approval by the Institutional Review Board (IRB)/Ethics Committee. All enrolled patients are required to provide written informed consent before participation. It is anticipated that this study will provide a new, effective, and minimally invasive treatment option that preserves bladder function and quality of life for patients with high-risk NMIBC, while also preliminarily investigating the mechanism of action of the TECIC model.

Sex

All

Minimum age

18 Years

Maximum age

85 Years

Inclusion Criteria:

1. Age between 18 and 85 years old, gender not restricted;
2. Clinically diagnosed as patients with bladder tumors, and classified as high-risk non-muscle-invasive bladder cancer through biopsy or TURBT staging.

   \* High-risk non-muscle bladder cancer is defined as meeting any of the following criteria: ① T1 stage tumor; ② High-grade urothelial carcinoma; ③ Simultaneously meeting: multiple, recurrent and diameter \> 3cm bladder cancer;
3. The number of tumors is no more than 5;
4. Have the intention to preserve the bladder;
5. Voluntarily sign the informed consent form and be able to cooperate throughout the trial.

Exclusion Criteria:

1. Preoperative imaging indicated involvement of organs around the bladder (such as ureters, prostate, rectum, etc.), the pelvic or abdominal wall, or lymph node metastasis (N1) and distant metastasis (M1) stage;
2. Preoperative imaging indicated hydronephrosis, pathology suggested carcinoma in situ or diagnostic TURBT indicated diffuse tumor growth during the procedure;
3. Known to be allergic to chemotherapy drugs and/or immunotherapy drugs;
4. Complicated with severe infectious diseases such as bacteremia and toxemia;
5. Complicated with severe coagulation dysfunction;
6. Suffering from serious diseases such as heart, brain, lung, liver, kidney, etc., and unable to tolerate surgery;
7. Suffering from other malignant tumors;
8. Pregnant or lactating women;
9. Complicated with severe complications such as urethral stenosis that cannot tolerate cystoscopy surgery;
10. Complicated with prohibited medications, including systemic anti-tumor drugs and immunosuppressants;
11. Participating in other clinical trials simultaneously;
12. Other situations that the investigator considers inappropriate for participating in this clinical trial.