Radical Nephroureterectomy With vs Without Template Lymph Node Dissection in High-Risk Upper Tract Urothelial Carcinoma (T-LND UTUC)

Официальное название

Clinical Efficacy and Safety of Radical Nephroureterectomy With Versus Without Template Lymph Node Dissection in High-Risk Upper Tract Urothelial Carcinoma: A Multicenter, Prospective, Randomized Controlled Clinical Trial

Обзор

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.

Подробное описание

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：

1. Primary Objectives:

1. 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. 2. 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. 2. Secondary Objectives:

1. To compare non-urothelial tract recurrence-free survival (NU-RFS), intravesical recurrence-free survival (IFS), and cancer-specific survival (CSS) between the two groups. 2. To establish a lymph node metastasis (pN+) mapping profile for different UTUC tumor locations using template-based LND. 3. Exploratory Objectives:

1. To identify molecular biomarkers predictive of prognosis using bulk RNA sequencing of prospectively collected tumor tissues. 2. 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:

1. Standardization of LND templates based on tumor location, enhancing surgical consistency and pathological staging. 2. Incorporation of biomarker and radiomic analyses to explore predictive signatures for lymph node involvement and survival. 3. A multicenter design ensuring generalizability and sufficient power to detect clinically meaningful differences in survival outcomes. 4. Potential to establish LND as a standard of care for high-risk UTUC, thereby informing future guidelines and improving oncologic outcomes.

Вмешательства

• Процедура Template Lymph Node Dissection
  A systematic and anatomic-based lymph node dissection performed during radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). The dissection boundaries are strictly defined by a pre-specified template according to the primary tumor location: renal hilum+para-aortic (left hilar and paraaortic) or renal hilum+para-caval (right hilar, paracaval, and interaortocaval) for renal pelvis/upper ureter; extended to common/external iliac for mid-ureter; and pelvic (common, external,
• Процедура Selective Lymph Node Resection
  A diagnostic procedure performed during radical nephroureterectomy (RNU). It does not involve a systematic template dissection. The surgeon will only remove intraoperatively identified suspicious and radiographic lymphadenopathy (\>1 cm in the short-axis diameter). The primary goal is pathological staging rather than therapeutic clearance of a nodal basin.

Первичные конечные точки

• Disease-Free Survival (DFS) [Срок оценки: From date of randomization until the date of first documented progression, recurrence, or death from any cause, assessed up to 5 years. (Assessments: every 3 months for the first 2 years, then every 6 months for years 3-5.)]
• Overall Survival (OS) [Срок оценки: From date of randomization until the date of death from any cause, assessed up to 5 years. (Assessments: every 3 months.)]
• Incidence and Severity of Postoperative Complications (Perioperative Safety) [Срок оценки: From the date of surgery until 30 days post-operation.]

Вторичные конечные точки (4)

• Non-Urothelial Tract Recurrence-Free Survival (NU-RFS) [Срок оценки: From date of randomization until the date of first documented non-urothelial recurrence or death, assessed up to 5 years. (Assessments: every 3 months for the first 2 years, then every 6 months for years 3-5.)]
• Intravesical Recurrence-Free Survival (IFS) [Срок оценки: From date of randomization until the date of first documented intravesical recurrence or death, assessed up to 5 years. (Assessments: cystoscopy every 6 months for the first 2 years, then as per protocol.)]
• Cancer-Specific Survival (CSS) [Срок оценки: Time Frame: From date of randomization until the date of death due to urothelial carcinoma, assessed up to 5 years. (Assessments: every 3 months.)]
• Lymph Node Metastasis Map [Срок оценки: At time of surgery (from final pathological report, approximately 4 weeks post-operation)]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Tianjin Medical University Second Hospital — Тяньцзинь

Публикации

• Hsieh HC, Wang CL, Chen CS, Yang CK, Li JR, Wang SS, Cheng CL, Lin CY, Chiu KY. The prognostic impact of lymph node dissection for clinically node-negative upper urinary tract urothelial carcinoma in patients who are treated with radical nephroureterectomy. PLoS One. 2022 Dec 1;17(12):e0278038. doi: 10.1371/journal.pone.0278038. eCollection 2022. PMID 36454803
• Bobjer J, Gerdtsson A, Abrahamsson J, Baseckas G, Bergkvist M, Blackberg M, Brandstedt J, Jancke G, Hagberg O, Kollberg P, Lundstrom KJ, Lofgren A, Nyberg M, Rian Martensson L, Saemundsson Y, Stahl E, Sorenby A, Warnolf A, Liedberg F. Location of Retroperitoneal Lymph Node Metastases in Upper Tract Urothelial Carcinoma: Results from a Prospective Lymph Node Mapping Study. Eur Urol Open Sci. 2023 S PMID 38020529
• Li X, Cui M, Gu X, Fang D, Li H, Qin S, Yang K, Zhu T, Li X, Zhou L, Gao XS, Wang D. Pattern and risk factors of local recurrence after nephroureterectomy for upper tract urothelial carcinoma. World J Surg Oncol. 2020 May 30;18(1):114. doi: 10.1186/s12957-020-01877-w. PMID 32473636
• Zareba P, Rosenzweig B, Winer AG, Coleman JA. Association between lymph node yield and survival among patients undergoing radical nephroureterectomy for urothelial carcinoma of the upper tract. Cancer. 2017 May 15;123(10):1741-1750. doi: 10.1002/cncr.30516. Epub 2017 Feb 2. PMID 28152158
• Huang J, Qian H, Yuan Y, Cai X, Chen Y, Zhang J, Kong W, Wu X, Cao M, Huang Y, Chen H, Xue W. Prospective Clinical Trial of the Oncologic Outcomes and Safety of Extraperitoneal Laparoscopic Extended Retroperitoneal Lymph Node Dissection at Time of Nephroureterectomy for Upper Tract Urothelial Carcinoma. Front Oncol. 2022 Feb 24;12:791140. doi: 10.3389/fonc.2022.791140. eCollection 2022. PMID 35280720
• Zhai TS, Jin L, Zhou Z, Liu X, Liu H, Chen W, Lu JY, Yao XD, Feng LM, Ye L. Effect of lymph node dissection on stage-specific survival in patients with upper urinary tract urothelial carcinoma treated with nephroureterectomy. BMC Cancer. 2019 Dec 12;19(1):1207. doi: 10.1186/s12885-019-6364-z. PMID 31830927
• Messer J, Lin YK, Raman JD. The role of lymphadenectomy for upper tract urothelial carcinoma. Nat Rev Urol. 2011 May 24;8(7):394-401. doi: 10.1038/nrurol.2011.78. PMID 21606972
• Roscigno M, Brausi M, Heidenreich A, Lotan Y, Margulis V, Shariat SF, Van Poppel H, Zigeuner R. Lymphadenectomy at the time of nephroureterectomy for upper tract urothelial cancer. Eur Urol. 2011 Oct;60(4):776-83. doi: 10.1016/j.eururo.2011.07.009. Epub 2011 Jul 14. PMID 21798659

Идентификаторы

NCT: NCT07321210 · TLND-UTUC

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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