Overview
The goal of this clinical trial is to learn if a more thorough lymph node removal surgery, called "Template Lymph Node Dissection," can help prevent cancer from returning and help patients live longer, compared to removing only a few enlarged lymph nodes, in patients with high-risk kidney cancer. The main questions it aims to answer are:
Do patients who receive template lymph node dissection live longer without their cancer returning (Disease-Free Survival)? Do patients who receive template lymph node dissection live longer overall (Overall Survival)? Is the more extensive lymph node surgery as safe as the limited surgery? Researchers will compare the Template Lymph Node Dissection group to the Limited Node Resection group to see the effects on cancer control and safety.
Participants will:
Be randomly assigned to one of the two surgical groups. Undergo surgery to remove their kidney and the assigned lymph nodes. Attend regular follow-up visits with imaging scans (like CT or MRI) for the first 5 years after surgery to monitor if the cancer returns.
Be followed for their overall survival status for up to 10 years.
Description
Research Background:
Renal cell carcinoma (RCC) remains a significant urological malignancy with rising global incidence. Radical nephrectomy (RN) is the standard curative treatment for localized disease. The therapeutic value of lymph node dissection (LND) in RCC, however, remains controversial. The EORTC 30881 trial demonstrated no survival benefit for RN with LND in clinically node-negative (cN0) patients, leading to its omission in contemporary guidelines. However, this trial predominantly included low-risk patients with a low incidence of pathological nodal involvement (4.0%), rendering it underpowered to evaluate LND efficacy in high-risk populations. Conversely, robust retrospective evidence suggests that in patients with high-risk features-such as advanced T-stage, large tumor size, sarcomatoid differentiation, or venous thrombus-more extensive LND may confer a therapeutic benefit by eradicating micrometastatic disease and improving cancer-specific survival. The advent of effective adjuvant immunotherapy (e.g., pembrolizumab) further underscores the need for accurate nodal staging and re-evaluation of LND's role. This prospective, randomized controlled trial aims to definitively assess the oncological benefit and safety of template-based LND in a rigorously selected high-risk RCC cohort.
Research Objectives:
Primary Objectives:
To compare the impact of RN combined with template lymph node dissection versus RN alone on overall survival (OS) and disease-free survival (DFS) in patients with high-risk RCC.
To evaluate and compare the surgical safety profiles of both approaches, including perioperative complications (graded by Clavien-Dindo classification), operative time, intraoperative blood loss, and length of hospital stay.
Secondary Objectives:
To compare cancer-specific survival (CSS) between the two groups. To quantify the number of lymph nodes retrieved and the incidence of nodal metastases within predefined anatomical templates (renal hilum, para-aortic, paracaval, and interaortocaval regions).
Exploratory Objectives:
To identify molecular biomarkers predictive of nodal metastasis or prognosis using Bulk-RNA sequencing of prospectively collected tumor and blood samples.
To develop a predictive nomogram for lymph node metastasis integrating radiomic features from triple-phase abdominal CT, MRI, tumor characteristics, and clinical symptoms.
Study Methodology:
This is a prospective, open-label, multicenter, randomized controlled trial. A total of 220 eligible patients with high-risk RCC-defined as cT3-4N0-1M0 or M1 disease rendered no evidence of disease (NED) after local therapy-will be randomized in a 1:1 ratio.
Intervention Group (Arm A): Patients will undergo RN plus template LND. The template for left-sided tumors includes lymph nodes from the diaphragmatic crus to the aortic bifurcation (anterior and lateral to the aorta), including the renal hilar nodes. For right-sided tumors, the template extends from the hepatic edge of the inferior vena cava (IVC) to the iliac bifurcation, encompassing paracaval, precaval, and interaortocaval nodes, including the renal hilum.
Control Group (Arm B): Patients will undergo RN with resection only of radiologically or intraoperatively detected lymph nodes ≥1 cm.
Randomization will be performed centrally and stratified by clinical nodal status (cN0 vs. cN1), prior metastatic status (M0 vs. M1→NED), type of renal cell carcinoma (clear cell RCC vs. non-clear cell RCC), and participating center.
Surgical approach (open, laparoscopic, or robot-assisted) will be at the surgeon's discretion. Postoperative adjuvant therapy with toripalimab (an anti-PD-1 agent) may be offered per patient preference, with one cycle provided free of charge by the study.
Endpoints and Statistical Analysis:
Primary endpoints are DFS and OS. Secondary endpoints include CSS, nodal yield and metastatic rate, and safety. DFS is defined as the time from randomization to recurrence, second primary RCC, or death from any cause. OS is defined as time from randomization to death from any cause. Time-to-event endpoints will be analyzed using Kaplan-Meier methods and compared with the log-rank test. Cox proportional hazards models will be used for multivariable analysis. Categorical variables will be compared using chi-square tests, and continuous variables with t-tests. A sample size of 220 provides 90% power to detect a 21.5% absolute improvement in 5-year OS (76% vs. 54.5%) at a two-sided α of 0.05, accounting for a 10% dropout rate.
- Innovation
This study addresses a critical evidence gap by prospectively evaluating template LND in a meticulously defined high-risk RCC population, including those with M1 NED status-a subgroup with particularly poor prognosis. It employs a standardized, anatomically defined "template" LND to ensure surgical quality and consistency across multiple centers. Furthermore, the study integrates contemporary biomarker and radiomic analyses to explore predictive tools for nodal metastasis and prognosis, which could personalize future surgical and adjuvant strategies. By conducting this trial in the era of adjuvant immunotherapy, it will elucidate whether LND provides independent therapeutic benefit beyond its staging role.
Eligibility
Inclusion Criteria:
- Signed informed consent form.
- Age \> 18 years.
- Candidate for radical nephrectomy with or without lymph node dissection.
- High-risk renal cell carcinoma defined as: At least ONE of: Clinical stage cT3-4 N0-1 M0 (AJCC 8th ed); OR radiologically visible lymph node \>1cm; OR M1 disease rendered no evidence of disease (NED) after local therapy; OR radiologically determined rT4 stage. OR at least TWO of: Renal vein or inferior vena cava tumor thrombus; OR nuclear grade 3-4 or sarcomatoid differentiation or coagulative necrosis; OR tumor size \>= 10cm; OR hematuria and/or local symptoms.
- Measurable disease as per RECIST v1.1.
- ECOG performance status of 0 or 1.
- Adequate bone marrow, renal, and hepatic function.
- For women and men of childbearing potential, agreement to use effective contraception during the study period.
Exclusion Criteria:
- Prior radiotherapy, chemotherapy, major surgery, or targeted therapy for RCC.
- Concurrent other active malignancy (except controlled malignancies not affecting 2-year survival).
- Candidate for partial nephrectomy or ablation per multidisciplinary team assessment.
- Preoperative imaging indicates unresectable regional lymph nodes.
- renal tumors or known hereditary RCC syndrome.
- Diagnosis of any other active malignancy within the past 5 years.
- Active autoimmune disease or history of autoimmune disease.
- Use of immunosuppressive agents within 2 weeks prior to enrollment.
- Poorly controlled cardiac or clinical symptoms.
- Coagulopathy or bleeding tendency.
- Active gastrointestinal conditions with risk of bleeding or perforation.
- History of significant bleeding or thromboembolic events within specified timeframes.
- Active infection or unexplained fever \>38.5°C.
- Abdominal fistula, gastrointestinal perforation, or abscess within 4 weeks prior.
- History of pulmonary fibrosis, interstitial lung disease, or severely impaired pulmonary function.
- Known immunodeficiency or active hepatitis.
- Participation in another clinical trial within 1 month.
- Known history of drug abuse or alcohol addiction.
- Inability or unwillingness to bear the self-paid portion of examination and treatment costs.
- Any condition that, in the investigator's judgment, may compromise patient safety or study conduct.
