Fluorescent Sentinel Lymph Node Identification in Colon Carcinoma Using Submucosal Bevacizumab-800CW. (IBIZA-1)

A Pilot Study to Assess the Safety and Feasibility of Fluorescent Sentinel Lymph Node Identification in Colon Carcinoma Using Submucosal Bevacizumab-800CW.

This prospective study aims to assess the safety and feasibility of lymph node identification using bevacizumab-800CW in patients with cT1-3N0-2 tumours, using peritumoral submucosal injections

Study Overview

• Status: Completed
• Conditions: Colorectal Neoplasms; Colonic Neoplasms; Sentinel Lymph Node; Fluorescence
• Intervention / Treatment: Procedure: Sentinel lymph node identification

Detailed Description

The current gold standard for the treatment of colon carcinoma consists of the surgical en-bloc resection of the colonic segment including the adjacent mesocolon containing the draining lymph nodes. Analysis of these lymph nodes is important, since lymph node status is one of the most important prognostic factors determining the use of adjuvant chemotherapy. Although patients with tumour stage I and II do not have lymph node metastases, 15-20% develop recurrent disease. Several studies suggest that ultrastaging techniques such as immunohistochemistry (IHC) or reverse transcriptase polymerase chain reaction (RT-PCR) using multilevel slicing results in upstaging of 14-18% of patients, due to newly found (micro)metastasis. Furthermore, several studies indicate that these micrometastases are correlated with a significantly poorer prognosis, subsequently suggesting that this subgroup of patients might benefit of adjuvant chemotherapy. Therefore, the most recent Dutch guidelines advice the use of adjuvant chemotherapy in this "upstaged" group, although evidence is still lacking.

However, ultrastaging techniques are labour-intensive and costly, and therefore not suitable for analyses of all lymph nodes that have been collected during segmental colectomy. Sentinel lymph node (SLN) identification in colon carcinoma has been proposed to overcome this problem by identifying the first order draining lymph node(s) of the tumour, which have the highest chance of containing metastatic tumour cells. Several studies aimed at SLN identification in colon carcinoma have been published, however, early studies using radio-guided or blue-dye guided SLN identification, showed relatively high rates of false negatives with consequent low sensitivity rates. Since mesocolon is rather fatty tissue, visualization of conventional dyes is difficult. Indocyanine green (ICG), which can be visualized using near infrared (NIR), has been put forward since it is known to penetrate relatively deep into living tissue.

Nevertheless, results of SLN identification using ICG remain unsatisfying with high false-negative rates and low sensitivity. Most likely this is due to the fact that these studies also included large cT3-cT4 tumours and patients with massive lymph node involvement. Which are factors known to interfere with lymph drainage patterns. Furthermore, subserosal injections were frequently used, while it is suggested that submucosal injections might result in better sensitivity of the procedure. In the FLUOR-SLN-ICG pilot study, we successfully conducted SLN identification in patients with ICG.

Recently, more research is conducted in tumour-targeted tracers as they have many advantages compared to ICG. For example, tumour-targeted tracers can be preoperatively administered which aid logistics, binds to tumour and metastases, thus allowing more time for uptake in patients with larger tumours and lymph node metastases. These properties may result in increased accuracy and would be more broadly applicable compared to ICG. Furthermore, tumour-targeted tracers can also be administrated intravenously and potentially identify lymph node metastases without having to perform a colonoscopy. However, administration via colonoscopy of tumour-targeted tracers for the detection of lymph node metastases in colon carcinoma has not been performed yet, and intravenous administration would be a step after administration via colonoscopy.

Therefore this prospective study aims to assess the safety and feasibility of lymph node identification using bevacizumab-800CW in patients with cT1-3N0-2 tumours, using peritumoral submucosal injections.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Utrecht
    • Amersfoort, Utrecht, Netherlands, 3813TZ
      • Meander Medisch Centrum

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Oral and written informed consent (IC)
• Aged 18 years and older
• Patients with pathologically confirmed and/or suspected cT1-3N0-2M0 colon carcinoma.

Exclusion Criteria:

• Distant metastasis
• Suspicion of cT4 disease based on pre-operative assessment
• Metastatic or T4 disease discovered during intraoperative staging
• Pregnancy, lactation or a planned pregnancy during the course of the study
• Previous colon surgery, excluding appendectomy.
• Contra-indication for laparoscopic/robotic surgery
• Inadequately controlled hypertension with or without current antihypertensive medication.
• Within 6 months prior to inclusion: myocardial infarction, TIA, CVA, pulmonary embolism, unstable angina pectoris, or uncontrolled chronic hepatic failure.
• Regarding Bevacizumab: Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies. Or an allergy for it's components (Trehalose dehydrate, sodium phosphate, polysorbate 20, water for injections)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• 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: Sentinel lymph node detection after submucosal bevacizumab-800CW injection; Therefore this prospective study aims to assess the safety and feasibility of lymph node identification using bevacizumab-800CW in patients with cT1-3N0-2 tumours, using peritumoral submucosal injections.	Procedure: Sentinel lymph node identification; Therefore this prospective study aims to assess the safety and feasibility of lymph node identification using bevacizumab-800CW in patients with cT1-3N0-2 tumours, using peritumoral submucosal injections.; Other Names: SLN

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification rate of SLN(s) or lymph node metastases	Defined as the number of patients in which a SLN or lymph node metastases were detected due to fluorescence during surgery and/or pathology assessment divided by the total number of procedures. We conclude that the study is a feasible if: We are to detect fluorescence in lymph nodes in 3 out of 5 patients (regardless of the presence of metastases); And/or we are able to detect lymph node metastases with fluorescence, or if fluorescence is higher in lymph node metastases compared to tumour-negative lymph nodes.	During surgery
Safety of SLN identification	The rate of adverse events related to bevacizumab-800CW (injection) will be measured. This is defined as the number of adverse events related towards bevacizumab-800CW/total number of procedures.	Measured till 90 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amount of fluorescence in lymph node metastases compared to lymph node without metastases	Fluorescence measured in the Oddysey flatbed scanner	3 months (after fluorescence measurement)
false-negative SLNs	The SLNs are negative whereas the non-sentinel nodes (NSNs) were positive (number).	3 months (after pathological examination)
true-negative SLNs	Both the SLNs and NSNs are negative (number).	3 months (after pathological examination)
sensitivity	The number of patients with a positive SLN / the total number of node positive patients (n, %).	3 months (after pathological examination)
upstaged patients	The number of patients with SLNs positive for micro- or macrometastases by serial slicing and IHC / the number of patients who were node negative by H&E examination (n, %).	3 months (after pathological examination)
aberrant lymph node status	The number of patients with aberrant lymph nodes, and the status of these lymph nodes considering micro- or macrometastases.	3 months (after pathological examination)
accuracy	(The total number of patients with a positive SLN + the number of patients with a true-negative SLN) / number of patients with an identified SLN (n, %).	3 months (after pathological examination)
negative predictive value	The number of true negative SLNs / (true negative + false negative SLNs).	3 months (after pathological examination)
number of SLNs identified	Number of SLN identified (number).	3 months (after pathological examination)

Collaborators and Investigators

• Sponsor: Meander Medical Center
• Investigators: Principal Investigator: Esther Consten, prof. dr., Meander Medisch Centrum

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2022
• Primary Completion (Actual): February 1, 2023
• Study Completion (Actual): June 1, 2023

Study Registration Dates

• First Submitted: July 20, 2022
• First Submitted That Met QC Criteria: August 10, 2022
• First Posted (Actual): August 11, 2022

Study Record Updates

• Last Update Posted (Actual): July 7, 2023
• Last Update Submitted That Met QC Criteria: July 6, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Colon cancer; Fluorescence; Sentinel lymph node; bevacizumab-800CW; bevacizumab-IRdye
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplasms; Colorectal Neoplasms; Colonic Neoplasms
• Other Study ID Numbers: R21.116; 2021-006700-32 (EudraCT Number)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

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