Confocal Laser Endomicroscopy During TransUrethral Resection for Improving BC Diagnosis and Treatment (CLETUR)

Confocal Laser Endomicroscopy During TransUrethral Resection for Improving Bladder Cancer Diagnosis and Treatment

A prospective monocenter diagnostic accuracy study of Confocal Laser Endomicroscopy (CLE) for Bladder Cancer(BC) to assess two primary objectives:

1. The diagnostic accuracy of flexible probe-based confocal laser endomicroscopy (CLE) compared to histopathology of the resection specimen.
2. The diagnostic accuracy of CLE-based assessment of the surgical radicality of the resection bed (radical vs irradical) in comparison with histopathology of a biopsy of the resection bed.

All patients with a papillary bladder tumor on cystoscopy will be included in this trial.

Study Overview

• Status: Completed
• Conditions: Bladder Cancer; CLE
• Intervention / Treatment: Device: Confocal Laser Endomicroscopy (CLE)

Detailed Description

Rationale:

Initial evaluation of gross hematuria consists of White Light Cystoscopy (WLC). Urine cytology combined with contrast imaging of the upper urothelial tract is performed when a bladder tumor is seen. Follow up of non-muscle invasive bladder carcinoma (NMIBC) after initial treatment consists of similar steps. When a suspected lesion is visualized, a transurethral resection of the bladder tumor (TURBT) is performed for therapeutic and diagnostic purposes. TURBT is considered to be the gold standard for diagnosis of urothelial carcinoma of the bladder (UCB). High recurrence rates of UCB after TURBT are reported, leading to repetitive surgery and high costs. In certain cases of high grade UCB a second look TURBT has proven to be beneficial after primary resection to ensure radical resection. Furthermore, recent research suggests that active surveillance for low-grade bladder tumors is safe. Confocal laser endomicroscopy (CLE), a high resolution optical imaging technique that can be used in combination with endo-urological procedures, seems promising to improve diagnosis of urothelial cancer, possibly without the need for immediate transurethral resection to obtain histological confirmation. CLE characteristics of UCB have been determined and validated using rigid probes, which are incompatible with flexible cystoscopes used for outpatient cystoscopies. With the present study, we aim to assess the diagnostic value of flexible probe based CLE for diagnosis and grading of UCB. Furthermore to possibly prevent second look TURBT in the future,an assessment of CLE features of the resection bed using a rigid CLE-probe will be performed.

Objective:

Primary objectives:

This study is two-fold and, therefore, has two primary objectives:

1. Investigating the diagnostic accuracy of CLE (Cystoflex™F probe) during flexible cystoscopy for diagnosis and grading of urothelial carcinoma of the bladder.
2. To investigate the diagnostic potential of CLE (Cystoflex™ UHD-R probe) for the assessment of the surgical radicality after transurethral resection of a bladder tumor (after TURBT)

Secondary objective:

- To construct a convolutional neural network for computer aided assessment of CLE images for diagnosis and grading of UCB.

Study design:

This is a prospective monocenter, observational diagnostic accuracy study. Diagnostic accuracy study to compare the CLE-based diagnosis with the histopathologic findings.

Study population: All patients >18 years old with a papillary bladder tumor who are planned for TURBT are eligible for this study. We will include 60 patients in this pilot study.

Intervention: At the operation theatre, before performing a TURBT for the standard clinical care, we introduce a flexible cystoscope to map the bladder, then we record CLE images of the index lesion using the Cystoflex™F. Subsequently, we replace the flexible scope by the (rigid) resectoscope. We acquire additional images with the Cystoflex™ UHD-R rigid probe. We perform the TURBT. After completion of the TURBT, we introduce the Cystoflex™ UHD-R probe again for imaging of the resection bed. At a later stage correlation with a standard biopsy of the resection bed will be performed.

For CLE imaging, a fluorescent contrast agent (fluorescein) will be used intravesically and intravenously, respectively, to temporarily stain the extracellular matrix of the urothelium. We will introduce fluorescein for intravesical use through a bladder catheter and rinse the fluorescein out of the bladder after an indwelling time of 5-10 minutes. Before CLE measurement of the resection bed we will administer fluorescein intravenously.

Main study parameters/endpoints:

1. Overall accuracy, sensitivity and specificity of flexible probe CLE-based diagnosis (benign vs malignant) and grading (low-grade versus high-grade) in comparison with the histopathology of the resection specimen.
2. Overall accuracy, sensitivity and specificity of CLE-based assessment of the surgical radicality of the resection bed (radical versus irradical) in comparison with the histopathology of the biopsy of the resection bed.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Participants will not benefit directly from this study. We hypothesize, however, that the results of this study will contribute to improvements in the diagnostic and surgical procedure for UCB. Outpatient-based cystoscopy with the potential diagnostic certainty of CLE-based grade assessment may enable active surveillance in low-risk UCB, and thus may even lead to a reduction in surgical procedures. We will introduce a CLE probe before TURBT via the working channel of the flexible cystoscope and hold it in direct contact with the bladder tumor to obtain CLE images. Before image acquisition of the bladder tumor we administer fluorescein intravesical, which is a fluorescent dye, used regularly intravenously in ophthalmatology. Before image acquisition of the resection bed we administer fluorescein intravenously. In patients not known with an allergy to this dye, this is a safe procedure. Patients with a known allergic reaction to fluorescein cannot participate in this study. Patients will be exposed to approximately 20 minutes of extra surgery time and the introduction of a flexible cystoscope compared to regular TURBT. As a result there is little burden to study participation for the patients. Adverse events are not expected based on previous experiences. The hospital's internal protocol for standard clinical care and histopathologic evaluation are not going to be affected by the study protocol.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1105AZ
      • Academic Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Display a papillary bladder tumor on cystoscopy.
• >18 years of age.
• Has given written informed consent.

Exclusion Criteria:

• Patients with a known allergy to fluorescein.
• Pregnancy or lactating women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic accuracy of flexible-probe based CLE(pCLE) for the diagnosis of urothelial carcinoma of the bladder (UCB)	Diagnostic accuracy (sensitivity, specificity, negative predictive value and positive predictive value) of flexible probe based CLE for the diagnosis (low-grade malignant, high-grade malignant) of urothelial carcinoma of the bladder.	Consensus panel within 12 months of start of study.
Diagnostic potential of probe based CLE for assessment of surgical radicality after transurethral resection of a bladder tumour (TURBT).	To investigate the diagnostic potential of CLE for the assessment of the surgical radicality (residual tumor/no residual tumor) after TURBT.	Consensus panel within 12 months of start of study.
Diagnostic potential of probe based CLE for assessment of depth of resection after transurethral resection of a bladder tumour (TURBT).	To investigate the diagnostic potential of CLE for depth of resection (according to the tissue in the resection margin: urothelium, submucosa, m. detrusor or perivesical fatty tissue) after TURBT.	Consensus panel within 12 months of start of study.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Computer aided assessment of pCLE images for diagnosis and grading of UCB	To construct a convolutional neural network for computer aided assessment of pCLE images for diagnosis and grading of UCB.	Within 24 months after starting study

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: J. R. Oddens, MD, PhD, Staff member of Urology Department

Study record dates

Study Major Dates

• Study Start (Actual): January 6, 2020
• Primary Completion (Actual): November 12, 2021
• Study Completion (Actual): November 12, 2021

Study Registration Dates

• First Submitted: March 19, 2020
• First Submitted That Met QC Criteria: March 1, 2022
• First Posted (Actual): March 10, 2022

Study Record Updates

• Last Update Posted (Actual): March 10, 2022
• Last Update Submitted That Met QC Criteria: March 1, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Bladder cancer; Diagnosis; CLE; Confocal Laser Endomicroscopy; Imaging techniques
• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Urinary Bladder Neoplasms
• Other Study ID Numbers: NL71360.018.19

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No