CTC Quantification During TURBT and PKVBT of Transitional Cell Carcinoma in Purging Fluid and Blood

Study Overview
=================
Brief Summary
-----------------
Transurethral resection of bladder tumor (TURBT) is usually performed in a piecemeal technique. Tumor fragmentation and cell spilling could be responsible for high recurrence rates. Circulating tumor cells (CTCs) have been shown to be a prognostic predictor in disease progression in transitional cell carcinoma. In the current study the investigators aim to quantify CTCs in purging fluid and blood for recurrent intermediate risk bladder cancer during surgery for two different methods: TURBT and Plasma-kinetic vaporization of bladder tumor (PKVBT). Also correlations for recurrence will be investigated for the two different surgical methods.

Detailed Description
-----------------
Bladder cancer is the 9th most commonly diagnosed cancer in men worldwide, with a standardized incidence rate of 9.0 per 100,000 person-years for men and 2.2 per 100,000 person-years for women. Amongst any caner entity, bladder cancer is the most expensive cancer regarding follow-up and life-time treatment costs due to the high probability of recurrence. Up to 85% of patients initially present with non muscle-invasive bladder cancer (NMIBC). Progression to muscle-invasive bladder cancer (MIBC) is up to 10-20%. NMIBC is characterized by a high risk of recurrence after transurethral resection of bladder tumor (TURBT): the 1-yr recurrence rate is 15-61% and the 5-yr recurrence rate is 31-78%. These numbers represent the heterogeneity of NMIBC. Against any existing oncological principle, during TURBT bladder tumors are resected in a piecemeal manner. This results in tumor fragmentation and floating cancer cells inside the bladder during surgery. These cells may have the ability to re-attach on and re-implant into the bladder wall and may be responsible for early disease recurrence which is commonly seen after initial surgery. It has been shown that tumor cells may access the circulatory system through cut vessels. Circulating tumor cells (CTCs) can be detected in up to 20% in T1 high grade disease and are commonly seen in metastasized disease. They have shown to be an independent predictor of disease progression and relapse in several studies and reflect biological aggressiveness. In the current study the investigators want to quantify CTCs for recurrent intermediate risk transitional cell carcinoma in purging fluid and blood for two different surgical methods: TURBT and Plasma-kinetic vaporisation of bladder tumors (PKVBT). Also correlations for recurrence will be investigated for the two different surgical methods. In 2 urological centers (LKH Hall, LKH Salzburg) participants with diagnosed intermediate risk recurrent transitional cell carcinoma of the bladder will be randomly enrolled for either TURBT or PKVBT. Before surgery CTCs will be analyzed in peripheral blood and purging fluid. (preoperative CTCs blood and purging fluid, morphological aspect of CTCs in purging fluid) After resection for TURBT and vaporization for PKVBT, a tumor ground biopsy will be taken for both groups. After coagluation, CTCs will again be drawn in peripheral blood (intraoperative CTCs blood). After completion of surgery an indwelling catheter is inserted and purging fluid is again analyzed (postoperative CTCs purging fluid, morphological aspect of CTCs in purging fluid). Blood is again taken on day 2 after surgery during the morning routine to assess CTCs after surgery (postoperative CTCs blood). Patients will be dismissed on earliest day 2 after surgery after indwelling catheter removal. Recurrence will be assessed during follow-up by cystoscopic controls (From 3 to 36 months after surgery). If recurrence is detected the study is terminated. If no recurrence is detected up to 36 months after surgery, the study is likewise terminated.

Official Title
-----------------
Circulating Tumor Cell (CTC) Quantification During Transurethral Resection (TURBT) and Plasma Kinetic Vaporisation (PKVBT) of Transitional Cell Carcinoma in Purging Fluid and Blood: a Randomized Controlled Trial

Conditions
-----------------
Transitional Cell Carcinoma, Urogenital Neoplasms, Circulating Tumor Cell, Neoplasms, Urinary Bladder Neoplasm

Intervention / Treatment
-----------------
* Device: Bipolar transurethral resection of bladder tumor (TURBT)
* Device: Bipolar transurethral plasma kinetic vaporization of bladder tumor (PKVBT)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: female and male patients recurrent bladder tumor preoperative cystoscopy CT or MRI scan of abdomen not older than 30 days prior to surgery without suspicion of advanced disease (MIBC, metastasis) max. non-invasive papillary tumor (pTa) staging in prior histology max. low grade grading in prior histology max. 5 lesions in actual cystoscopy (all < 3cm) exophytic tumors transitional cell cancer of urinary bladder patient able to give consent signed consent form Exclusion Criteria: initial tumor flat lesion > 3cm carcinoma in situ (CIS) in prior histology or suspicious CIS-finding in actual cystoscopy high grade grading in prior histology ≥ pT1 (tumor infiltration into subepithelial connective tissue) staging in prior histology > 5 lesions different entity from transitional cell carcinoma of urinary bladder prior radiation emergency surgery prior indwelling catheter (extraction < 1 week prior to surgery) pregnancy orthotopic neobladder

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Pilot trial with parallel group design and comparison of 2 established techniques (TURBT, PKVB)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: TURBT (Transurethral Resection of Bladder Tumor)<br>For patients undergoing bipolar transurethral resection, bladder tumor is resected in a piecemeal manner. | Device: Bipolar transurethral resection of bladder tumor (TURBT)<br>* Standard resection in piecemeal technique with standard bipolar cutting loop. (Storz medical, 27040 GP1)<br>|
| Active Comparator: PKVB (Plasma Kinetic Vaporization of Bladder Tumor)<br>For patients undergoing bipolar plasma kinetic vaporization of bladder tumor, bladder tumor is vaporized. | Device: Bipolar transurethral plasma kinetic vaporization of bladder tumor (PKVBT)<br>* Vaporization of bladder tumor with standard bipolar vaporization electrode. (Storz medical, 27040 NB)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| intraoperative CTC-number in blood [n/ml] | Circulating tumor cells (CTCs) are measured in 15ml of peripheral blood which is taken during surgery. CTCs are quantified via automated immunofluorescence-microscopy. CK20+, p53+, DAPI+ and CD45- cells will be classified transitional cancer CTCs. | During surgery: after evacuation of snippets for TURBT and after full vaporization for PKVBT. | 
| postoperative CTC-number in blood [n/ml] | Circulating tumor cells (CTCs) are measured in 15ml peripheral blood which is taken after surgery. CTCs are quantified via automated immunofluorescence-microscopy. CK20+, p53+, DAPI+ and CD45- cells will be classified transitional cancer CTCs. | 2nd postoperative day during morning routine. | 
| postoperative CTC-number in purging fluid [n/ml] | Circulating tumor cells (CTCs) are measured in purging fluid after the surgical intervention. After insertion of a new indwelling catheter the bladder is fully emptied and 100ml of sterile NaCl 0,9% is injected and extracted 5 times into and out of the bladder to mix CTCs. CTCs are quantified via automated immunofluorescence-microscopy. CK20+, p53+, DAPI+ and CD45- cells will be classified transitional cancer CTCs. | For both gruops (TURBT and PKVB) after insertion of indwelling catheter before finishing surgery. | 
| postoperative CTC morphology in purging fluid | Cytological morphology of CTCs in purging fluid. CTCs will be examined for both groups and their morphological aspect (e.g. vital, non-vital, necrotic, deformed) is classified. | After insertion of indwelling catheter before finishing the surgery. | 
| pre-to-intraoperative change of CTC-number in blood [n/ml] | The difference of the preoperative and intraoperative CTC-number in blood is calculated. Due to the intervention in both groups a difference in CTC-number is to be expected. | Preoperative CTCs will be taken right before the start of surgery. Intraoperative CTCs will be taken after evacuation of snippets for TURBT and after full vaporization for PKVBT. | 
| pre-to-postoperative change of CTC-number in blood [n/ml] | The difference of the preoperative and postoperative CTC-number in blood is calculated. Due to the intervention in both groups a difference in CTC-number is to be expected. | Preoperative CTCs will be taken right before the start of surgery. Postoperative CTCs will be taken on day 2 after surgery during the morning routine. | 
| intra-to-postoperative change of CTC-number in blood [n/ml] | The difference of the intraoperative and postoperative CTC-number in blood is calculated. Due to the intervention in both groups a difference in CTC-number is to be expected. | Intraoperative CTCs will be taken after evacuation of snippets for TURBT and after full vaporization for PKVBT. Postoperative CTCs will be taken on day 2 after surgery during the morning routine. | 
| pre-to-postoperative change of CTC-number in purging fluid [n/ml] | The difference of the preoperative and postoperative CTC-number in purging fluid is calculated. Due to the intervention in both groups a difference in CTC-number is to be expected. | Preoperative CTCs in purging fluid are taken via an indwelling catheter right before start of the surgery. Postoperative CTCs in purging fluid are taken after insertion of a new indwelling catheter before finishing the surgery. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor recurrence [yes/no] | Tumor recurrence is evaluated between 3 months and 36 months after surgery with follow-up cystoscopy. | According to follow up cystoscopy at 3, 6, 12, 24, 36 months after intervention. | 
| Time to recurrence [days] | The time difference from date of surgery to date of cystoscopic detection of recurrence. Including analysis of influencing factors. | Through study completion, recurrence can occur within a maximum follow up of 36 months. | 
| preoperative CTC-number in purging fluid [n/ml] | Circulating tumor cells (CTCs) are measured in purging fluid before the surgical intervention. After insertion of an indwelling catheter the bladder is fully emptied and 100ml of sterile NaCl 0,9% is injected and extracted 5 times into and out of the bladder to mix CTCs. CTCs are quantified via automated immunofluorescence-microscopy. CK20+, p53+, DAPI+ and CD45- cells will be classified transitional cancer CTCs. | Right before surgery. | 
| preoperative CTC-number in blood [n/ml] | Circulating tumor cells (CTCs) are measured in 15ml peripheral blood which is taken right before surgery. CTCs are quantified via automated immunofluorescence-microscopy. CK20+, p53+, DAPI+ and CD45- cells will be classified transitional cancer CTCs. | Right before start of surgery. | 
| preoperative CTC morphology in purging fluid | Cytological morphology of CTCs in purging fluid. CTCs will be examined for both groups and their morphological aspect (e.g. vital, non-vital, necrotic, deformed) is classified. | Right before start of surgery. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bladder cancer, NMIBC, CTC, Circulating tumor cell, Transurethral resection, Plasma kinetic vaporization, TURBT, PKVB