Template Lymph Node Dissection for Tumor Control in High-Risk Renal Cell Carcinoma: A Prospective, Open-Label, Multicenter, Randomized Controlled Trial
Phase: NA
Conditions: Renal Cell Carcinoma (Kidney Cancer)
Sponsor: Tianjin Medical University Second Hospital

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Template Lymph Node Dissection for Tumor Control in High-Risk
Renal Cell Carcinoma: A Prospective, Open-Label, Multicenter,
Randomized Controlled Trial
Study Protocol
Protocol Number:
Protocol Version
Number:
V1.0
Protocol Version
Date:
August 10, 2025
Principal
Investigators:
Sponsor:
Tianjin Medical University Second Hospital
Confidential Document
Unauthorized use, disclosure, publication, or any other form of disclosure is prohibited

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Principal Investigator Signature Page
I confirm that this clinical study is an Investigator-Initiated Trial (IIT). The
principal investigator of this clinical study will simultaneously assume the relevant
responsibilities of both the investigator and the sponsor as stipulated in GCP.
I will diligently fulfill the responsibilities of both the sponsor and the investigator
in accordance with GCP, personally participate in, and directly guide this clinical
study. I confirm this study protocol. I agree to perform the relevant duties in
accordance with Chinese laws, the Declaration of Helsinki, GCP, and this clinical
study protocol. I confirm that this study protocol and any subsequent protocol
amendments must be approved by the Ethics Committee before implementation. I will
keep this study protocol and documents and information related to this study
confidential.
Research Unit:Tianjin Medical University Second Hospital
__________________
_________________
Principal Investigator
(Printed Name)
Principal Investigator
(Signature)
Signature Date
(Year/Month/Day)

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Protocol Summary
Study Title
Template Lymph Node Dissection for Tumor Control in High-Risk Renal Cell
Carcinoma: A Prospective, Open-Label, Multicenter, Randomized Controlled Trial
Protocol Number
Protocol Version
Number
V1.0
Protocol Version
Date
2025-08-10
Clinical Study
Type
Registrational Clinical Trial
Clinical Study
Registration
Investigator-Initiated Trial, IIT
Clinical Trial
Approval
Document
Clinical Study
Unit
Tianjin Medical University Second Hospital
Funder
Study Population
Patients with renal cell carcinoma (RCC) amenable to nephrectomy (clinical stage
cT3-4N0-1M0), as well as M1 patients whose metastatic lesions can be rendered M0
status (No Evidence of Disease, NED) with local therapy.
Study Objectives
Primary Objectives:
1) To
compare
the
impact
of
nephrectomy
combined
with
template
lymphadenectomy versus nephrectomy alone on Overall Survival (OS) and
Disease-Free Survival (DFS) in patients with high-risk RCC at risk of recurrence or
progression.
2) To evaluate and compare the surgical safety between the two groups, including
perioperative complications (graded by the Clavien-Dindo classification), operation
time, intraoperative blood loss, and hospital stay.

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Secondary Objectives:
1）To compare Cancer-Specific Survival (CSS) between the two groups.
2）To quantify the number of lymph nodes retrieved and the rate of lymph node
metastasis (pN+%) in the following specific template regions: right renal hilum,
para-supravenous caval region, para-infravenous caval region, left renal hilum,
para-supra-aortic region, para-aortic region.
Exploratory Objectives:
1）To utilize prospectively collected tumor tissues and Bulk-RNA sequencing
technology to explore potential molecular biomarkers predictive of lymph node
metastasis or prognosis.
2）To develop a nomogram for predicting lymph node metastasis based on
prospectively collected radiomics data (triple-phase contrast-enhanced abdominal
CT, non-contrast MRI), tumor size/location, retroperitoneal/renal hilar lymph node
size/location, and clinical symptoms.
Study Design
This is a multicenter, prospective, open-label, randomized controlled clinical trial.
Sample Size
220 cases
Study Endpoints
Primary Endpoints:
1) Disease-Free Survival (DFS):Defined as the time from randomization until the
first documented occurrence of disease recurrence (local, regional, or distant
metastasis), a second primary renal cancer, or death from any cause.
2) Overall Survival (OS):Defined as the time from randomization to death from any
cause. For subjects lost to follow-up, the last follow-up date will be used as the
censoring time.
3)Perioperative complications, intraoperative blood loss, ECOG Performance
Status, and hospital stay.
Secondary Endpoints:
1) Cancer-Specific Survival (CSS)
2) Number of lymph nodes retrieved and lymph node positive rate (pN+%) from
each defined template region.ymph node metastasis map: Positive rate (pN+%) of
lymph nodes at each template dissection site.
3) Exploration of biomarkers for DFS, CSS, and OS based on Bulk-RNA data.
4) Prediction of lymph node metastasis: Developing a predictive nomogram based
on prospectively collected radiomics data from triple-phase contrast-enhanced
abdominal CT, plain MRI, tumor size/location, retroperitoneal/hilar lymph node
size/location, and clinical symptoms.

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Surgery
1) Randomization Groups:
Experimental Intervention (Group A): Nephrectomy + Template Lymph Node
Dissection.
Control Intervention (Group B): Nephrectomy + resection of radiologically or
intraoperatively visible lymph nodes >1cm.
2) Lymph Node Dissection Template:
Left-side Template: Lymphatic tissue anterior and lateral to the abdominal aorta
from the diaphragmatic crus to the aortic bifurcation, including the hilar lymph
nodes.
Right-side Template: Lymphatic tissue surrounding the inferior vena cava (IVC)
and between the IVC and abdominal aorta from the liver edge of the IVC to the iliac
vein bifurcation, including the hilar lymph nodes.
3) Surgical Requirements:
The surgical approach (open, laparoscopic, or robot-assisted) will be determined
by the surgeon based on the patient's specific condition and the surgeon's expertise.
The extent of lymph node dissection must strictly adhere to the protocol-defined
template.
Study Procedures
This clinical study consists of three main phases:Screening, Treatment, and
Follow-up.
Screening Period:
1) From signing the Informed Consent Form (ICF) until randomization.
2)The screening period should not exceed 14 days.
Treatment Period:
1)Surgical treatment after randomization. Perioperative data will be recorded up to
30 days post-surgery.
2) At the end of the treatment period, the investigator will recommend subsequent
therapy. Based on patient preference, adjuvant therapy may be chosen for 1 year (17
cycles). If the patient agrees to adjuvant therapy and chooses Toripalimab, one cycle
of the drug will be provided free of charge by the study.
Follow-up Period:
1)Safety Follow-up: Safety follow-ups will be conducted at the end of each adjuvant
treatment cycle and post-surgery, tracking Adverse Events (AEs) until resolution,
stabilization, or return to baseline.
2)urvival Follow-up: Conducted every 3 weeks to document survival status until
subject death, loss to follow-up, withdrawal of ICF, completion of 2-year survival
follow-up, or study end, whichever occurs first.
3)Tumor Progression Follow-up: Begins post-surgery. Survival and recurrence data
are collected via outpatient reviews and telephone follow-ups. Imaging (CT/MRI)
will be performed every 3 months in the first year, every 6 months from years 2-5,
and annually after 5 years until patient death, loss to follow-up, withdrawal of ICF,
or study end (maximum follow-up 10 years), for DFS, OS, and CSS assessment.
Inclusion Criteria
Patients meeting all of the following criteria may be enrolled:

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1) Sign a written Informed Consent Form (ICF).
2) Age >18 years at the time of ICF signing, either sex.
3) Preoperative typical imaging evaluation and systemic health assessment indicate
suitability for nephrectomy and nephrectomy combined with template lymph node
dissection.
4) Clinical stage cT3-4 N0-1 M0 or M1 disease rendered M0 (NED) after local
therapy (AJCC 8th ed.), specifically meeting at least ONE of the following high-risk
criteria:
a)Presence of radiologically visible lymph nodes >1cm.
b) M1 disease rendered radiologically M0 (NED) after local therapy.
c) Radiologically determined rT4 stage.
OR meeting at least TWO of the following high-risk criteria:
a)Renal vein or inferior vena cava tumor thrombus.
b)Nuclear grade 3-4 and/or sarcomatoid differentiation and/or coagulative tumor
necrosis.
c)Tumor size ≥10 cm.
d)Hematuria and local symptoms (including microscopic/gross hematuria, pain,
etc.).
5) Measurable disease as per RECIST v1.1 criteria.
6) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
7) Adequate organ function (without use of blood components/growth factors within
14 days):Normal bone marrow reserve function.Bone marrow: Neutrophils
≥
1,500/mm³, Platelets ≥100,000/mm³, Hemoglobin ≥9 g/dL (5.6 mmol/L).Renal:
Serum creatinine ≤1.5 mg/dL and/or Creatinine clearance ≥60 mL/min.Hepatic:
Bilirubin ≤1.5 × ULN, AST & ALT ≤1.5 × ULN.
8) For non-sterilized or premenopausal women: Use of medically approved
contraception during and for 3 months after the study; negative serum/urine HCG
test within 7 days before enrollment; non-lactating. For non-sterilized men:
Agreement to use medically approved contraception with their spouse during and
for 3 months after the study.
9) Subject voluntarily joins the study, has good compliance, and agrees to safety and
survival follow-up.
Exclusion Criteria
Patients with any of the following cannot be enrolled:
1) Prior radiotherapy, chemotherapy, long-term/high-dose corticosteroid therapy,
surgery, or molecular targeted therapy for RCC.
2) History or presence of another active malignancy (except for those controlled

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with minimal impact on 2-year survival).
3) Deemed more suitable for partial nephrectomy or ablation by Multidisciplinary
Team (MDT) assessment.
4) Preoperative imaging indicates unresectable regional lymph nodes: massive
confluent nodal masses or complete encasement of aorta/IVC precluding safe
separation.
5) Known bilateral RCC or hereditary RCC syndrome (e.g., VHL, Birt-Hogg-Dubé).
6) Diagnosis of other active malignancies within the past 5 years (except cured basal
cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in situ
with no recurrence within 5 years).
7) Any active autoimmune disease or history of autoimmune disease (e.g.,
autoimmune
hepatitis,
interstitial
pneumonia,
uveitis,
enteritis,
hepatitis,
hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism; Vitiligo or
childhood
asthma
in
complete
remission
is
allowed;
asthma
requiring
bronchodilators is excluded).
8) Use of immunosuppressive agents for immunosuppression purposes within 2
weeks prior to enrollment.
9) Poorly controlled cardiac symptoms/diseases: a) NYHA Class II+ heart failure, b)
Unstable angina, c) Myocardial infarction within 1 year, d) Clinically significant
supraventricular/ventricular arrhythmia requiring treatment/intervention.
10) Coagulopathy (PT>16s, APTT>43s, TT>21s, Fbg<2g/L), bleeding tendency, or
undergoing thrombolysis/anticoagulation therapy.
11) Pre-existing conditions with risk of bleeding (e.g., esophageal varices, active
gastric/duodenal ulcer, ulcerative colitis, portal hypertension) or active bleeding
from unresected tumors, or other conditions deemed by investigator to risk GI
bleeding/perforation.
12) History of severe bleeding (>30 mL within 3 months), hemoptysis (>5 mL fresh
blood within 4 weeks), or thromboembolic events (including stroke/TIA) within 12
months.
13) Active infection or unexplained fever >38.5°C during screening/before first
dose.
14) Abdominal fistula, gastrointestinal perforation, or abdominal abscess within 4
weeks before surgery.
15) History or current objective evidence of pulmonary fibrosis, interstitial
pneumonia,
pneumoconiosis,
radiation
pneumonitis,
drug-related
pneumonia,
severely impaired pulmonary function, etc.
16) Congenital or acquired immunodeficiency (e.g., HIV), or active hepatitis (liver

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enzymes not meeting inclusion criteria; for HBV: HBV DNA ≥10⁴
copies/mL;
for HCV: HCV RNA ≥10³ copies/mL). Chronic HBV carriers with DNA ≥2000
IU/ml (≥10⁴
copies/ml) can be enrolled only if antiviral therapy is administered
during the study.
17) Concurrent participation in another clinical study or within 1 month of ending a
previous study; likely to receive other systemic anti-tumor therapy during the study.
18) Known history of drug abuse, alcohol abuse, or drug addiction.
19) Inability or unwillingness to bear the cost of self-paid examinations/treatments.
20) Investigator judgment for exclusion due to other reasons potentially leading to
study termination (e.g., other severe diseases including psychiatric, severe lab
abnormalities, social/family factors affecting safety or data/sample collection).
Withdrawal
Criteria
1) The subject or their legal representative requests early withdrawal.
2) The investigator, based on professional judgment, believes that continued
participation may harm the subject's health.
3) Cancellation of the planned radical nephroureterectomy or inability to perform it
for any reason.
4) Subject is lost to follow-up or unable to complete key protocol-specified
follow-up due to poor compliance.
5) The investigator deems it necessary to withdraw the subject.
All withdrawn subjects should be followed up according to the study protocol, and
follow-up results recorded, unless the patient withdraws consent and refuses
follow-up.
Concomitant
Medications/
Therapies
Permitted Concomitant Medications/Therapies:
Supportive care; topical analgesics; all adverse reactions should be actively treated,
especially those related to postoperative complications.
Safety Evaluation
Safety evaluation indicators include adverse events observed during the study,
changes in laboratory tests, vital signs, ECG, lower extremity venous ultrasound
results
before
and
after
treatment,
intraoperative
blood
loss,
postoperative
complications, time to discharge, etc.
Record the name, start and end time, measures taken, and outcome of all AEs during
the study. Grade severity of AEs according to NCI CTCAE v5.0; grade severity of
postoperative complications according to Clavien-Dindo classification
Efficacy
Evaluation
1) Assess postoperative DFS and PFS (if applicable) according to RECIST v1.1
criteria via regular imaging (chest CT, lower abdomen contrast-enhanced CT/MRI),
record OS.

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2) Evaluate surgical outcomes based on pathological results and perioperative
conditions.
3) Identify efficacy biomarkers using Bulk-RNA data.
Statistical
Methods
1) Primary endpoints DFS, OS and secondary survival endpoints CSS will be
estimated using the Kaplan-Meier method and compared between groups using the
log-rank test.
2) Multivariate analysis will be performed using the Cox proportional hazards
model.
3) Categorical variables (e.g., complication rate, pN+ rate) will be compared using
the chi-square test.
4) Continuous variables (e.g., operative time, blood loss) will be compared using the
t-test.
5) In this study, unless otherwise specified, data will be summarized using
descriptive statistics according to the following general principles. Measurement
data will be summarized using mean, standard deviation, median, maximum, and
minimum; count data will be summarized using frequency and percentage.
6) Safety Analysis: Adverse events will be summarized using frequency and
percentage; laboratory tests (blood routine, blood biochemistry, etc.), ECOG, vital
signs, and ECG will be summarized using descriptive statistics.
7) Quality of Life Analysis: Paired t-test will be used to compare changes.
All tests are two-sided, and a p-value <0.05 is considered statistically significant.
Treatment
Discontinuation
Defined as termination of treatment for any reason, e.g., inability to perform the
surgical procedure, intolerance, or early withdrawal. Safety follow-up must still be
completed after treatment discontinuation to assess AE resolution.
Study Completion
Defined as the last subject completing follow-up, or early withdrawal from
follow-up.
Study Termination
1) The investigator identifies unexpected, significant, or unacceptable risks to
subjects.
2) A major design flaw is discovered during study execution.
3) The experimental treatment is ineffective, or the investigator judges that
continuing the study is meaningless.
4) The research institution or ethics committee decides to terminate the clinical
study early.
Study Timeline
Estimated date of first subject enrollment: September 2025
Estimated date of last subject enrollment: September 2028

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Estimated study completion date: August 2033