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
Phase: NA
Conditions: Upper Tract Urothelial Carcinoma, Lymph Node Dissection
Sponsor: Tianjin Medical University Second Hospital

1
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
Study Protocol
Protocol Number:
Protocol Version
Number:
V1.0
Protocol Version
Date:
August 20, 2025
Principal
Investigators:
Sponsor:
Tianjin Medical University Second Hospital
Confidential Document
Unauthorized use, disclosure, publication, or any other form of disclosure is prohibited.

2
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)

3
Protocol Summary
Study Title
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
Protocol Number
Protocol Version
Number
V1.0
Protocol Version
Date
2025-08-04
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 clinically diagnosed with high-risk (cT2-4N0-1M0 or cT1N1M0) upper
tract
urothelial
carcinoma
(UTUC)
who
are
planned
to
undergo
radical
nephroureterectomy.
Study Objectives
Primary Objectives:
1) Compare the impact of radical nephroureterectomy combined with template
lymph node dissection versus radical nephroureterectomy alone on disease-free
survival (DFS) and overall survival (OS) in patients with high-risk non-metastatic
UTUC.
2) Evaluate and compare the surgical safety between the two groups, including
perioperative complications (according to Clavien-Dindo classification), operative
time, intraoperative blood loss, and hospital stay.

4
Secondary Objectives:
1）Compare non-urothelial tract recurrence-free survival (NU-RFS), intravesical
recurrence-free survival (IV-RFS), and cancer-specific survival (CSS) between the
two groups.
2）Establish a lymph node metastasis (pN+) map for UTUC at different sites in the
high-risk UTUC population through template lymph node dissection (LND).
Exploratory Objectives:
1）Utilize prospectively collected tumor tissues to explore molecular biomarkers
for predicting prognosis through Bulk-RNA sequencing.
2）Utilize
prospectively
collected
radiomics
data
from
renal
ureter
contrast-enhanced CT, tumor size/location, retroperitoneal/pelvic lymph node
size/location, and clinical symptoms to establish a nomogram for predicting lymph
node metastasis.
Study Design
This is a multicenter, prospective, open-label, randomized controlled clinical trial.
Sample Size
150 cases
Study Endpoints
Primary Endpoints:
1) Disease-free survival (DFS): Defined as the time from randomization to the first
recorded recurrence at any site (local, regional lymph nodes, distant metastasis),
new urothelial carcinoma in the contralateral upper tract or bladder, or death from
any cause, whichever occurs first. Overall survival (OS): Defined as the time from
randomization to the recorded death from any cause.
2) Perioperative complications, intraoperative blood loss, performance status
(Karnofsky score), and hospital stay.
Secondary Endpoints:
1) NU-RFS: Defined as the time from randomization to the first recorded local,
regional lymph node, distant metastasis recurrence, or death from any cause,
whichever occurs first. IV-RFS: Defined as the time from randomization to the first
recorded new urothelial carcinoma in the contralateral upper tract or bladder, or
death from any cause, whichever occurs first. CSS: Defined as the time from
randomization to the recorded death due to urothelial carcinoma.
2) Lymph node metastasis map: Positive rate (pN+%) of lymph nodes at each
template dissection site.
3) Identify efficacy biomarkers for DFS, OS, and CSS using Bulk-RNA sequencing
technology.

5
4) Lymph node metastasis prediction: Establish a nomogram for predicting lymph
node
metastasis
based
on
prospectively
collected
radiomics
data
from
whole-abdomen triple-phase contrast-enhanced CT, tumor size/location, lymph node
size/location at each template dissection site, and clinical symptoms.
Surgery
1) Randomization Groups:
Experimental Intervention (Group A): Nephroureterectomy + Template Lymph
Node Dissection.
Control Intervention (Group B): Nephroureterectomy + Dissection of only lymph
nodes visible on imaging or intraoperatively (>1 cm).
2) Lymph Node Dissection Template (Group A only):
Renal Pelvis & Upper Ureter Tumors: Dissect renal hilum, para-aortic or para-caval
lymph nodes (depending on affected side). Superior border: level of the central
adrenal vein (right) or superior border of adrenal gland; Inferior border: bifurcation
of aorta or vena cava.
Mid-Ureter Tumors: Extend the dissection template downward from the renal
pelvis/upper ureter template to below the tumor level, including common iliac and
external iliac nodes.
Lower Ureter Tumors: Dissect pelvic lymph nodes, including common iliac,
external iliac, internal iliac, and obturator lymph node regions.
3) Surgical Requirements:
Surgical approach (open, laparoscopic, or robot-assisted) is determined by the
surgeon based on the patient's specific condition and technical expertise; the lymph
node dissection scope must strictly follow the protocol-defined template.
Radical Nephroureterectomy (RNU): Both groups require complete resection of the
affected kidney, perirenal fat, and the entire ureter, including a bladder cuff excision.
Lymph Node Dissection (LND):
Group A (Experimental): Must strictly execute the corresponding template lymph
node dissection based on tumor location.
Group B (Control): Template lymph node dissection is not performed. If clearly
enlarged suspicious lymph nodes (>1 cm) are found intraoperatively, resection of
visible lymph nodes is allowed for pathological staging, but template dissection is
not performed.
Study Procedures
This clinical study includes three main phases: screening, treatment, and follow-up.
Screening Period:
1) From signing informed consent until randomization.
2) The screening period should not exceed 14 days.
Treatment Period:
1) Surgery is performed after randomization, and perioperative data are recorded up
to 30 days postoperatively.
Follow-up Period:
1) Safety Follow-up: Subjects undergo safety follow-up postoperatively, tracking
adverse events (AEs) until resolution or stabilization, or return to baseline levels.
2) Survival Follow-up: Conducted every 3 months, recording survival status until
subject death, loss to follow-up, withdrawal of consent, completion of 5-year
survival follow-up, or study end, whichever occurs first.

6
3) Tumor Progression Follow-up: Starts postoperatively. Survival and recurrence
data are collected via outpatient review and telephone follow-up. Within 2 years
postoperatively: imaging (CT/MRI/US) and urinary cytology every 3 months,
cystoscopy every 6 months. Years 3-5: intervals extended to 6 months. After 5
years: annual review until patient death, loss to follow-up, withdrawal of consent, or
study end (maximum follow-up 10 years), for assessing DFS, CSS, and OS. (Within
5 years, contrast-enhanced CT/MRI annually, or as deemed necessary by the
investigator).
Inclusion Criteria
Patients meeting all of the following criteria may be enrolled:
1) Signed written Informed Consent Form (ICF).
2) Age >18 years at the time of signing ICF, either gender.
3) Clinical diagnosis of unilateral UTUC by imaging (contrast-enhanced CT or
MRI) and/or ureteroscopic biopsy/urinary cytology, and planned to undergo radical
nephroureterectomy.
4) Clinical assessment indicates that the tumor and regional lymph nodes can be
completely resected, and with at least one of the following high-risk features:
a) Locally advanced: Preoperative imaging assessment of cT2 stage or higher
(i.e., tumor invades muscularis propria or deeper).
b) High-grade: Preoperative ureteroscopic biopsy pathology confirms high-grade
urothelial carcinoma (or with squamous differentiation/sarcomatoid differentiation).
c)
Moderate
to
severe
hydronephrosis:
Ipsilateral
moderate
or
severe
hydronephrosis due to tumor obstruction.
d) Large tumor size: Maximum tumor diameter >2cm on imaging.
e) cN1: Imaging suggests regional lymph node short axis >1cm, and the
investigator judges it as resectable.
5) Measurable lesion according to RECIST v1.1 criteria.
6) Eastern Cooperative Oncology Group (ECOG) performance status score: 0~1.
7) Adequate function of major organs meeting the following requirements
(excluding use of any blood components or growth factors within 14 days): Normal
bone marrow reserve: neutrophils ≥1500/mm ³ , platelets
≥100,000/mm ³ ,
hemoglobin ≥5.6 mmol/L (9 g/dL); Normal renal function: serum creatinine ≤1.5
mg/dL and/or creatinine clearance ≥60 ml/min; Normal liver function: bilirubin
≤1.5xULN, AST & ALT ≤1.5xULN.
8) Non-sterilized or women of childbearing potential must use a medically approved
contraceptive method during the study treatment and for 3 months after treatment
ends
(e.g.,
IUD,
oral
contraceptives,
condoms);
Non-sterilized
women
of
childbearing potential must have a negative serum or urine HCG test within 7 days

7
before study enrollment; must be non-lactating; Non-sterilized men of childbearing
potential must agree to use a medically approved contraceptive method with their
partner during the study treatment and for 3 months after treatment ends.
9) The subject voluntarily joins the study, has good compliance, and cooperates with
safety and survival follow-up.
Exclusion Criteria
Patients with any of the following cannot be enrolled:
1) Previous receipt of any anti-tumor therapy for UTUC, including chemotherapy,
radiotherapy, immunotherapy, or targeted therapy.
2) Previous or concurrent muscle-invasive bladder urothelial carcinoma.
3) Preoperative imaging assessment indicates unresectable regional lymph nodes:
lymph nodes fused into a massive conglomerate, or completely encasing the
abdominal aorta/inferior vena cava/pelvic vessels preventing safe separation.
4) Known bilateral UTUC or genetic diseases that clearly increase the risk of
contralateral upper tract tumors, such as Lynch Syndrome.
5) Diagnosis of other active malignancies within the past 5 years (except for cured
skin basal cell carcinoma, skin squamous cell carcinoma, or cervical carcinoma in
situ with no recurrence within 5 years).
6) Presence of any active autoimmune disease or history of autoimmune disease
(including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis,
enteritis,
hepatitis,
hypophysitis,
vasculitis,
nephritis,
hyperthyroidism,
hypothyroidism; subjects with vitiligo or childhood asthma that has completely
resolved and requires no intervention in adulthood may be included; asthma
requiring bronchodilator intervention cannot be included).
7) Subject is using immunosuppressants for immunosuppressive purposes and
continues use within 2 weeks prior to enrollment.
8) Poorly controlled cardiac clinical symptoms or diseases, such as: a) NYHA Class
II or above heart failure; b) Unstable angina; c) Myocardial infarction within 1 year;
d) Clinically significant supraventricular or ventricular arrhythmias requiring
treatment or intervention.
9) Coagulation abnormalities (PT>16s, APTT>43s, TT>21s, Fibrinogen<2g/L),
bleeding tendency, or receiving thrombolytic or anticoagulant therapy.
10) Preoperative presence of esophageal varices, active gastric/duodenal ulcer,
ulcerative colitis, portal hypertension, or other gastrointestinal diseases, or active
bleeding from an unresected tumor, or other conditions deemed by the investigator
likely to cause gastrointestinal bleeding or perforation.
11) History or current presence of severe hemorrhage (>30ml within 3 months),
hemoptysis (>5ml of fresh blood within 4 weeks), or thromboembolic events

8
(including stroke and/or transient ischemic attack) within 12 months.
12) Active infection at the time of screening, or unexplained fever >38.5°C during
screening or before the first dose.
13) Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 4 weeks prior to surgery.
14) Objective evidence of history or current presence of pulmonary fibrosis,
interstitial
pneumonia,
pneumoconiosis,
radiation
pneumonitis,
drug-related
pneumonia, severely impaired pulmonary function, etc.
15) Congenital or acquired immunodeficiency, such as HIV infection, or active
hepatitis (liver enzymes not meeting inclusion criteria; for hepatitis B: HBV DNA
≥10^4 copies/ml; for hepatitis C: HCV RNA ≥10^3 copies/ml); chronic HBV
carriers with HBV DNA ≥2000 IU/ml (≥10^4 copies/ml) can only be enrolled if
they receive concurrent antiviral therapy during the trial.
16) Subject is participating in another clinical study or less than 1 month has passed
since the end of the previous clinical study; subject may receive other systemic
anti-tumor therapy during the study period.
17) Known history of drug abuse, alcoholism, or drug addiction; subject is unable or
unwilling to bear the self-paid portion of examination and treatment costs; the
investigator considers exclusion from the study for other reasons, e.g., other serious
diseases (including mental illness) requiring combined treatment, severe laboratory
abnormalities, or family/social factors that may affect subject 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.

9
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.
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 NU-RFS, IV-RFS,
and 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.

10
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: August 2027
Estimated study completion date: August 2032