Clinical trial NCT02607709: Lymphadenectomy in Urothelial Carcinoma
Official title: Lymphadenectomy in Urothelial Carcinoma in the Renal Pelvis and Ureter
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: NA
Conditions: Ureteral Neoplasms
Lead sponsor: Zealand University Hospital
Sponsor class: OTHER
First posted: 2015-11-18
Enrollment: 366
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Age above 18 years
2. Locally advanced high grade urothelial carcinoma in the renal pelvis or upper 2/3 of the ureter (Clinical stage \> T1)
3. Patient with ECOG performance score of 2 and less.
4. Able to give informed consent

Exclusion Criteria:

1. Clinical suspicion of non-muscle invasive UUTUC
2. Metastatic urothelial carcinoma for the renal pelvis or upper 2/3 of the ureter
3. Inability to understand written consent forms or give consent

Primary outcomes:
measure: Recurrence free survival
timeFrame: Five years
Secondary outcomes:
measure: Incidence of metastasis
timeFrame: Five years
Other outcomes:
measure: Complications
timeFrame: Within 30 days after operations
Locations:
city: Roskilde
country: Denmark
facility: Roskilde Hospital
Study officials:
affiliation: Roskilde University Hospital
name: Nessn H Azawi, MB.Ch.B.
role: STUDY_CHAIR
References:
citation: Holmang S, Johansson SL. Bilateral metachronous ureteral and renal pelvic carcinomas: incidence, clinical presentation, histopathology, treatment and outcome. J Urol. 2006 Jan;175(1):69-72; discussion 72-3. doi: 10.1016/S0022-5347(05)00057-1.
citation: Hall MC, Womack S, Sagalowsky AI, Carmody T, Erickstad MD, Roehrborn CG. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology. 1998 Oct;52(4):594-601. doi: 10.1016/s0090-4295(98)00295-7.
citation: Olgac S, Mazumdar M, Dalbagni G, Reuter VE. Urothelial carcinoma of the renal pelvis: a clinicopathologic study of 130 cases. Am J Surg Pathol. 2004 Dec;28(12):1545-52. doi: 10.1097/00000478-200412000-00001.
citation: Lughezzani G, Jeldres C, Isbarn H, Shariat SF, Sun M, Pharand D, Widmer H, Arjane P, Graefen M, Montorsi F, Perrotte P, Karakiewicz PI. A critical appraisal of the value of lymph node dissection at nephroureterectomy for upper tract urothelial carcinoma. Urology. 2010 Jan;75(1):118-24. doi: 10.1016/j.urology.2009.07.1296. Epub 2009 Oct 28.
citation: Kondo T, Nakazawa H, Ito F, Hashimoto Y, Toma H, Tanabe K. Primary site and incidence of lymph node metastases in urothelial carcinoma of upper urinary tract. Urology. 2007 Feb;69(2):265-9. doi: 10.1016/j.urology.2006.10.014.
citation: Kondo T, Hara I, Takagi T, Kodama Y, Hashimoto Y, Kobayashi H, Iizuka J, Omae K, Ikezawa E, Yoshida K, Tanabe K. Possible role of template-based lymphadenectomy in reducing the risk of regional node recurrence after nephroureterectomy in patients with renal pelvic cancer. Jpn J Clin Oncol. 2014 Dec;44(12):1233-8. doi: 10.1093/jjco/hyu151. Epub 2014 Sep 30.
citation: Tanaka N, Kikuchi E, Kanao K, Matsumoto K, Kobayashi H, Ide H, Miyazaki Y, Obata J, Hoshino K, Shirotake S, Akita H, Kosaka T, Miyajima A, Momma T, Nakagawa K, Hasegawa S, Nakajima Y, Jinzaki M, Oya M. Metastatic behavior of upper tract urothelial carcinoma after radical nephroureterectomy: association with primary tumor location. Ann Surg Oncol. 2014 Mar;21(3):1038-45. doi: 10.1245/s10434-013-3349-z. Epub 2013 Nov 12.
citation: Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13. doi: 10.1097/01.sla.0000133083.54934.ae.