Overview
The goal of this clinical trial is to learn if adding a template lymph node dissection (TLND) to the standard surgery for upper tract urothelial cancer (UTUC) can improve patient survival and prevent the cancer from recurrence. The main questions it aims to answer are:
Do patients who receive standard surgery with LND live longer without their cancer returning? Is adding LND safe, and how does it affect surgery-related complications? Researchers will compare the group receiving standard surgery plus LND to the group receiving standard surgery alone to see if adding LND is more effective.
Participants will:
Be randomly assigned to one of the two surgical groups. Undergo their assigned surgery and recover in the hospital. Attend regular follow-up visits for checkups and scans for 5 years to monitor for cancer recurrence, with the possibility of long-term follow-up extending to 10 years.
Description
Background： Upper tract urothelial carcinoma (UTUC), encompassing renal pelvic and ureteral carcinomas, is a relatively rare but aggressive malignancy of the urinary system, accounting for 5-10% of all urothelial cancers. Radical nephroureterectomy (RNU) with bladder cuff excision remains the gold standard for treating non-metastatic UTUC. However, prognosis remains poor, particularly for patients with locally advanced disease, due to high rates of recurrence and metastasis. The role of concurrent lymph node dissection (LND) during RNU is one of the most debated topics in UTUC management. While LND is widely accepted in muscle-invasive bladder cancer for its diagnostic and therapeutic benefits, its utility in UTUC lacks high-level evidence. Current guidelines conditionally recommend LND for high-risk UTUC based largely on retrospective data, leading to significant heterogeneity in clinical practice. This multicenter, prospective, randomized controlled trial aims to definitively establish the clinical value of template-based LND in high-risk UTUC.
Objectives：
- Primary Objectives:
- To compare the impact of RNU plus template LND versus RNU alone on disease-free survival (DFS) and overall survival (OS) in patients with high-risk non-metastatic UTUC.
- To evaluate and compare the safety profiles of both approaches, including perioperative complications (graded by Clavien-Dindo), operative time, intraoperative blood loss, and length of hospital stay.
- Secondary Objectives:
- To compare non-urothelial tract recurrence-free survival (NU-RFS), intravesical recurrence-free survival (IFS), and cancer-specific survival (CSS) between the two groups.
- To establish a lymph node metastasis (pN+) mapping profile for different UTUC tumor locations using template-based LND.
- Exploratory Objectives:
- To identify molecular biomarkers predictive of prognosis using bulk RNA sequencing of prospectively collected tumor tissues.
- To develop a lymph node metastasis prediction nomogram based on radiomic data from contrast-enhanced CT, tumor characteristics, lymph node size/location, and clinical symptoms.
Methods：
This is a prospective, multicenter, open-label, randomized controlled trial. A total of 150 eligible patients with high-risk UTUC (cT2-4N0-1M0 or cT1N1M0) will be randomized in a 1:1 ratio to one of two arms:
Experimental Arm (A): RNU + template LND Control Arm (B): RNU + removal of only radiologically or intraoperatively detected lymph nodes \>1 cm Stratified randomization will be performed based on tumor location (renal pelvis/upper ureter, mid-ureter, lower ureter) and clinical nodal status (cN0 vs. cN1). Surgical approach (open, laparoscopic, or robotic) will be at the surgeon's discretion, but LND must adhere to predefined anatomical templates.
Patients will be followed for up to 10 years, with regular imaging, urine cytology, and cystoscopy according to a standardized schedule. DFS, OS, and other survival endpoints will be analyzed using Kaplan-Meier methods and Cox proportional hazards models. Safety will be assessed via Clavien-Dindo grading and monitoring of adverse events.
Innovation：
This trial addresses a critical evidence gap in UTUC management by providing the first high-level, prospective, randomized data on the therapeutic efficacy of template LND. Key innovative aspects include:
- Standardization of LND templates based on tumor location, enhancing surgical consistency and pathological staging.
- Incorporation of biomarker and radiomic analyses to explore predictive signatures for lymph node involvement and survival.
- A multicenter design ensuring generalizability and sufficient power to detect clinically meaningful differences in survival outcomes.
- Potential to establish LND as a standard of care for high-risk UTUC, thereby informing future guidelines and improving oncologic outcomes.
Eligibility
Inclusion Criteria:
Signed written informed consent form (ICF). Age \> 18 years at the time of ICF signing. Clinical diagnosis of unilateral Upper Tract Urothelial Carcinoma (UTUC) by imaging (enhanced CT or MRI) and/or ureteroscopic biopsy/urinary cytology, and scheduled to undergo Radical Nephroureterectomy (RNU).
Clinical assessment indicating that the tumor and regional lymph nodes are completely resectable, with at least one of the following high-risk features:
- Locally advanced: Preoperative imaging assessed as cT2 stage or higher (i.e., tumor invades muscularis propria or deeper).
- High-grade: Preoperative ureteroscopic biopsy pathology confirmed as high-grade urothelial carcinoma (or with squamous differentiation/sarcomatoid differentiation).
- Moderate or severe hydronephrosis: Ipsilateral moderate or severe hydronephrosis due to tumor obstruction.
- Large tumor size: Imaging measures maximum tumor diameter \> 2 cm.
- cN1: Imaging suggests regional lymph node short-axis diameter \> 1 cm, and the investigator judges it to be resectable.
Presence of at least one measurable lesion according to RECIST v1.1 criteria. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Adequate organ function meeting the following requirements (without use of any blood components or colony-stimulating factors within 14 days):
Bone marrow function: Neutrophils ≥ 1,500/mm³, Platelets ≥ 100,000/mm³, Hemoglobin ≥ 9 g/dL (5.6 mmol/L).
Renal function: Serum creatinine ≤ 1.5 mg/dL and/or Creatinine clearance ≥ 60 mL/min.
Liver function: Total bilirubin ≤ 1.5 × ULN, AST \& ALT ≤ 1.5 × ULN. For women of childbearing potential (WOCBP): Must agree to use a highly effective medically approved contraceptive method during the treatment period and for 3 months after treatment ends. A negative serum or urine pregnancy test within 7 days before enrollment is required; must be non-lactating. For non-sterilized male patients: Must agree to use effective contraception with their partner during the treatment period and for 3 months after treatment ends.
Subject voluntarily joins the study, has good compliance, and agrees to undergo safety and survival follow-up.
Exclusion Criteria:
Previous receipt of any anti-tumor therapy for UTUC, including chemotherapy, radiotherapy, immunotherapy, or targeted therapy.
History or concurrent presence of muscle-invasive bladder urothelial carcinoma. Preoperative imaging assesses regional lymph nodes as unresectable: lymph nodes fused into a massive conglomerate, or fully encasing the abdominal aorta/inferior vena cava/pelvic vessels preventing safe separation.
Known bilateral UTUC or hereditary diseases that definitively increase the risk of contralateral upper tract tumors, such as Lynch Syndrome.
Diagnosis of other active malignancies within the past 5 years (except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix which have been cured and show no recurrence within 5 years).
Presence of any active autoimmune disease or history of autoimmune disease. Current use of immunosuppressants for immunosuppressive purposes, continued within 2 weeks prior to enrollment.
Poorly controlled cardiac clinical symptoms or diseases. Coagulation abnormalities or bleeding tendency. Presence of specific active gastrointestinal conditions or uncontrolled tumor bleeding.
History of significant bleeding, hemoptysis, or thromboembolic events within specified timeframes.
Active infection or unexplained fever \> 38.5°C during screening or before the first dose.
Occurrence of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to surgery.
History or current objective evidence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, severely impaired pulmonary function, etc.
Congenital or acquired immunodeficiency. Participation in another clinical study within 1 month prior to enrollment, or potential receipt of other systemic anti-tumor therapy during the study period.
Known history of psychotropic drug abuse, alcohol abuse, or drug use. Inability or unwillingness to bear the out-of-pocket costs of examinations and treatments. Any other condition deemed by the investigator to make the subject unsuitable for participation.