Ex Vivo Tumor Visualization and Resection Margin Assessment Using Topically Applied Fluorescent Imaging Agents (SprayDye)

This is a proof-of-principle study, that uses freshly resected human solid tumor specimens to assess the performance of topically applied fluorescent imaging agents for the detection of tumor tissue and close / tumor-positive resection margins ex vivo. Surgery will be performed in conformity with hospital protocol. The study will not interfere with the standard clinical care.

Study Overview

• Status: Recruiting
• Conditions: Solid Tumor, Adult
• Intervention / Treatment: Drug: Topical application of a fluorescent imaging agent

Detailed Description

Surgical excision remains an integral part of curative-intent treatment for most solid tumors. The goal of surgical resection is to completely remove all tumor tissue. A tumor-positive or inadequate surgical resection margin, defined as cancer cells at or near (depending on tumor type) the edge of the resection specimen, has major prognostic implications and often necessitates additional treatments. These additional treatments are in turn associated with increased morbidity, complication risks, and healthcare costs.

To achieve a complete resection of the tumor, surgeons rely on visual inspection and palpation, sometimes assisted by localization or pathology techniques such as implanted (radioactive/magnetic) seeds and frozen section analysis. However, inadequate resection margin rates in solid tumors remain high, indicating current methods for intraoperative margin assessment are insufficient. They lack real-time feedback on the margin status of large tissue surface areas to guide additional resection.

A technique that could meet these requirements is tumor-targeted fluorescence imaging (FI). It combines the administration of a fluorescence imaging agent with the use of fluorescence light. This technique allows for real-time optical feedback by selectively highlighting tumor tissue that expresses certain molecular targets that bind the imaging agent or has certain characteristics that activate it.

Presently, the vast majority of fluorescence imaging agents under investigation for intraoperative tumor visualization and resection margin assessment have to be administered intravenously, hours or days prior to surgery. Very recently, new imaging agents have been designed that can be topically administered. Topically applied imaging agents allow for specimen-based (ex vivo) resection-margin assessment using FI, without the necessity to administer the probe to the patient. This approach offers several advantages: (I) ex vivo topical application on the resected specimen eliminates all toxicity risks, as the patient is not exposed to the imaging agent; (II) it is much more cost-effective. First of all, a lower imaging agent dose can be used because there is no systemic volume of distribution, and the probe is not metabolized and excreted. Secondly, toxicity testing and in-patient clinical trials are not required to use the ex vivo topical approach in clinical practice, which greatly reduces implementation time and costs; (III) the ex vivo topical approach is easier to implement in the current surgical workflow, and does not require the patient logistics needed for systemic administration.

In this proof-of-principle study, the investigators will investigate if topically applied fluorescent imaging agents can be used to visualize tumor tissue and detect inadequate resection margins ex vivo on freshly resected solid human tumors.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Stijn Keereweer, Dr; Phone Number: 0107041357; Email: s.keereweer@erasmusmc.nl
• Study Contact Backup: Name: Bo Zweedijk, Drs; Phone Number: 0107042985; Email: b.zweedijk@erasmusmc.nl

Study Locations

• Netherlands
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015 GD
      • Recruiting
      • Erasmus University Medical Center
      • Contact: Stijn Keereweer, MD PhD
      • Principal Investigator: Stijn Keereweer, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with a biopsy-proven solid tumor, scheduled for surgery at the Erasmus Medical Center.
2. Signed and dated informed consent obtained before any study-related procedure is performed.

Exclusion Criteria:

1. Terminated surgical procedure.
2. No fresh specimen available.
3. Participation in a clinical trial for which the patient receives another fluorophore perioperatively.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Topical application of a fluorescent imaging agent; In this arm the investigators use the freshly resected human solid tumor specimens to assess the performance of topically applied fluorescent imaging agents for the detection of tumor tissue and close / tumor-positive resection margins ex vivo.	Drug: Topical application of a fluorescent imaging agent; The fluorescent imaging agent will be topically applied only onto the resection planes of the freshly resected tumor specimen. During incubation and after each washing steps, visible light and fluorescent overlay images will be acquired using a fluorescence sensitive camera system.; Other Names: fluorescent imaging agent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor-to-background ratio (TBR) of the fluorescence signal on the resection specimen surface and on 3-5 mm thick tissue slices.	TBR was calculated by drawing a region of interest (ROI) spanning the tumor, and another in adjacent (muscle) tissue using the imaging system's integrated software	through study completion, up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Imaging agent fluorescence signal intensity on close / tumor-positive resection planes compared with (wide) tumor-negative resection planes, as confirmed by histopathology	Signal intensity was determined from a region of interest (ROI) drawn in close / tumor-positive resection planes as well as (wide) tumor-negative resection planes, and comparing them using the imaging system's integrated software.	through study completion, up to 3 years
Difference in tumor-to-background ratio (TBR) between different imaging time windows	TBR was calculated for different imaging time windows, and compared.	through study completion, up to 3 years
The concordance between the presence of tumor cells and fluorescence signal	Overlaying fluorescence images with corresponding H&E slides	through study completion, up to 3 years
Depth of the fluorescence signal on 4-μm tissue slides	Penetration depth of topically applied fluorescent imaging agents was determined from fluorescence images	through study completion, up to 3 years

Collaborators and Investigators

• Sponsor: Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: November 20, 2023
• First Submitted That Met QC Criteria: February 27, 2024
• First Posted (Actual): March 5, 2024

Study Record Updates

• Last Update Posted (Actual): August 28, 2024
• Last Update Submitted That Met QC Criteria: August 27, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Fluorescence imaging
• Other Study ID Numbers: 11272

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

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