Guided by light: Optimizing surgical excision of oral cancer using real-time fluorescence imaging

Head and neck cancer (HNC) is the 9th most common tumor worldwide, a third of
them arising in the oral cavity. Complete tumor resection of oral cancer is the
most important surrogate marker for survival. Precise margin delineation is
imperative in the delicate head and neck region where wider resections
inevitably lead to increased morbidity and loss of functionality.
In current practice, intraoperative assessment of the tumor-free margin is
dependent on visual appearance and palpation of the tumor. We have reported
inadequate surgical margins in up to 85% of patients with oral cancer, which is
unacceptable. Therefore, new intraoperative visualization techniques are
required to assess tumor margins in real-time and to guide surgical removal of
oral cancer with adequate tumor-free margins while retaining maximal
functionality.
Fluorescence imaging (FLI) using near-infrared light has recently emerged as a
revolutionary technique to provide real-time visualization of tumor tissue,
enabling image-guided surgery. Tumor-specific fluorescent targeting agents are
systemically injected preoperatively and real-time FLI is performed using a
dedicated intraoperative camera system. In this study, we will test the use of
cRGD-ZW800-1, a tumor-specific agent that targets integrins, for intraoperative
detection and margin delineation of oral cancer. Overexpression of a wide range
of integrin receptors is reported in HNC.
The overarching goal of this two-staged clinical trial is to improve adequate
resection of oral cancer.

This study has been transitioned to CTIS with ID 2024-512824-13-01 check the CTIS register for the current data.

The overarching goal of this study is to improve adequate resection of oral
cancer. We will perform a clinical trial to determine the optimal dose of
cRGD-ZW800-1 and to investigate the feasibility of intraoperative FLI to
adequately assess tumor margins in patients with oral cancer.

Primary Objective:
To improve adequate resection of oral cancer using fluorescent imaging
technology.
1. WP I: To determine the recommended dose for the highest tumor-to-background
ratio (TBR) of at least >2.0 using cRGD-ZW800-1 in oral cancer;
2. WP II: To increase the rate of adequate (i.e. >5mm clear) tumor resection
margins

This proposal describes a two-staged clinical trial to investigate the
feasibility of intraoperative FLI to adequately assess tumor margins in
patients with oral cancer using cRGD-ZW800-1. In WP-I, I will determine the
preferred dose of the agent for imaging of margins in oral cancer. The
signal-to-noise ratio will be determined in dose group A (n=7). After an
interim evaluation of this ratio, the second dose group B (n=7) will receive
either a higher or a lower dosage of the tracer. After inclusion of all
patients (n=14), the dose with the highest intraoperative signal-to-noise ratio
will be selected.

In WP-II, I will then add an expansion cohort (n=14) to the group of patients
that had received the selected dose in WP-I. In this group of 21 patients, I
then determine if FLI can improve the rate of adequate surgical resection
margins. As secondary research questions I will assess sensitivity,
specificity, positive and negative predictive values of FLI; colocalization
with immunohistochemistry; change in surgical management; incremental operation
time; and FLI of excised cervical lymph nodes.

Amendment (October 2023): After the first 7 inclusions in dose group A (0.05
mg/kg), it was decided to de-escalate to 0.01 mg/kg based on the very strong
signal. After including 3 patients with this dose, it was concluded during an
interim analysis that 0.01 mg/kg showed insufficient fluorescent signal, and
that it was not sensible to give this dose to another 4 patients. It was
decided to proceed with an intermediate dose, namely 0.025 mg/kg. The next 7
patients (dose group B) received this dose, which was found to be the ideal
dose after the completion of WP-1. Therefore, the extension cohort in WP-2
(n=14) received/are receiving 0.025 mg/kg.

I will measure fluorescence signal during the operation. Next, the surgeon will
perform the operation without using FLI. After the resection, I will perform
FLI of the specimen surface and surgical wound bed and mark any fluorescent
areas. Together with the pathologist, the surgeon then performs intraoperative
assessment (IOA) of the resection margins. If inadequate, a limited extra
resection of tissue is performed. Meanwhile, if I find fluorescent areas in the
wound bed, I will take frozen sections. Only if these show tumor cells, the
surgeon performs a limited extra resection. Postoperatively, I will perform FLI
of all tissues in a black box scanner and I correlate integrin-specific
targeting to immunohistochemistry.

Injection of cRGD-ZW800-1 within 48 hours before imaging/surgery

Patient burden:

1) Consideration to join scientific research at an emotionally heavy time of
diagnosis and treatment of cancer;
2) Administration of single-dose of fluorescent tracer;
3) Additional measurements of vital functions, ECG and laboratory testing after
administration;
4) Minimal risk of allergic reaction to fluorescent tracer;
5) Expected extension of operating time of 10-15 minutes;

Potential patient benefit:

Small chance of higher surgical success rate.