Lymphadenectomy in Urothelial Carcinoma

Study Overview
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Brief Summary
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Two out of three tumours in the upper urinary tract are located in the renal pelvis. Muscle-invasive urothelial carcinoma is probably more common among tumours in the upper urinary tract compared to tumours in the urinary bladder. Thus, muscle-invasive tumours represent approximately 45 % of renal pelvic tumours compared to 25 % of tumours within the urinary bladder. As in the bladder, lymph node metastases are rare in non-muscle invasive disease. Information regarding indications, extent and possible curative potential is currently lacking for lymphadenectomy in conjunction with nephroureterectomy for urothelial carcinoma in the upper urinary tract (UUTUC). There are, however, retrospective series with survival data for patients with lymph node metastasis that report long term survival after surgery as monotherapy [4] with similar survival proportions as in bladder cancer with lymph node metastases after radical cystectomy. A retrospective study from Tokyo was expanded to the only available prospective study, where 68 patients with UUTUC were submitted to template-based lymphadenectomy. Another retrospective study by the same Japanese group, showed that 5-year cancer-specific and recurrence-free survival was significantly higher in the complete lymphadenectomy group than in the incomplete lymphadenectomy or without lymphadenectomy groups. Tanaka N et al. reported recurrence rate after nephroureterectomy without lymphadenectomy at 1 and 3 years were 18.9 and 29.8 %, respectively.

Detailed Description
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Background: Two out of three tumours in the upper urinary tract are located in the renal pelvis. Muscle-invasive urothelial carcinoma is probably more common among tumours in the upper urinary tract compared to tumours in the urinary bladder. Thus, muscle-invasive tumours represent approximately 45 % of renal pelvic tumours compared to 25 % of tumours within the urinary bladder. As in the bladder, lymph node metastases are rare in non-muscle invasive disease. Information regarding indications, extent and possible curative potential is currently lacking for lymphadenectomy in conjunction with nephroureterectomy for urothelial carcinoma in the upper urinary tract (UUTUC). There are, however, retrospective series with survival data for patients with lymph node metastasis that report long term survival after surgery as monotherapy with similar survival proportions as in bladder cancer with lymph node metastases after radical cystectomy. A retrospective study from Tokyo was expanded to the only available prospective study, where 68 patients with UUTUC were submitted to template-based lymphadenectomy. Another retrospective study by the same Japanese group, showed that 5-year cancer-specific and recurrence-free survival was significantly higher in the complete lymphadenectomy group than in the incomplete lymphadenectomy or without lymphadenectomy groups. Tanaka N et al. reported recurrence rate after nephroureterectomy without lymphadenectomy at 1 and 3 years were 18.9 and 29.8 %, respectively. Hypothesis: Complete lymphadenectomy during nephroureterectomy because of invasive urothelial carcinoma may reduce the incidence of lymph nodes metastasis, local recurrence, distant metastasis and improve the cancer survival rate. Purpose: To evaluate the influence of complete lymphadenectomy on recurrence and cancer specific survival rate compared to limited or no lymphadenectomy. Primary endpoint/analysis: Recurrence free survival at five-year postoperative. Secondary endpoints: Incidence of lymph node metastases, local recurrence and/or distant metastasis, cancer specific and overall survival at one, three and five-year postoperative. Complications rate according to Clavien classification within the first thirty days postoperatively. Another endpoint/analysis: Multivariate analysis of possible preoperative risk factors for lymph node metastases (tumour size, preoperative urinary cytology, lymph node enlargement on CT, PET-CT positivity) and postoperative risk factors for lymph node metastases (stage, grade, tumour diameter, presence of necrosis in the tumour (none; <10%; >10% of total tumour area), number of lymph nodes excised). Design: Prospectively randomized to template based lymphadenectomy or not, in patients with clinically muscle-invasive UUTUC in the renal pelvis or upper 2/3 of the ureter. One to one, controlled clinical trial. Patients will be randomly allocated into two groups, 183 patients in each group. Group A will be scheduled to receive routine standard open or robot assisted nephroureterectomy without lymphadenectomy except for clinically enlarged. Group B will be scheduled to received mapped lymphadenectomy in conjugation with nephroureterectomy.

Official Title
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Lymphadenectomy in Urothelial Carcinoma in the Renal Pelvis and Ureter

Conditions
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Ureteral Neoplasms

Intervention / Treatment
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* Procedure: Lymphadenectomy in conjugation with nephroureterectomy
* Procedure: Nephroureterectomy without lymphadenectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age above 18 years Locally advanced high grade urothelial carcinoma in the renal pelvis or upper 2/3 of the ureter (Clinical stage > T1) Patient with ECOG performance score of 2 and less. Able to give informed consent Exclusion Criteria: Clinical suspicion of non-muscle invasive UUTUC Metastatic urothelial carcinoma for the renal pelvis or upper 2/3 of the ureter Inability to understand written consent forms or give consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Nephroureterektomy<br>scheduled to receive routine standard open or robot assisted nephroureterectomy without lymphadenectomy | Procedure: Nephroureterectomy without lymphadenectomy<br>* Removing the kidney, ureter and bladder cuff<br>|
| Experimental: Nephroureterektomy + Lymphadenectomy<br>scheduled to received mapped lymphadenectomy in conjugation with nephroureterectomy | Procedure: Lymphadenectomy in conjugation with nephroureterectomy<br>* Lymphadenectomy (intervention group only): Lymphadenectomy performs in four fractions on the right side and two fractions on the left side according to Dissection template (Appendix 1). Renal hilar nodes are included in fraction 1 and 3, respectively.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence free survival |  | Five years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of metastasis |  | Five years |