Real time Molecular Fluorescence and Narrow Band Imaging for detection of the Primary Cancer Lesion in Patients with a Metastatis of Unknown Primary Tumor in the Head and Neck

Cancer of unknown primary (CUP) is defined as the presence of histologically
proven metastatic disease for which the site of origin cannot be identified at
the time of diagnosis. In this study, we focus squamous cell carcinoma
metastases in the upper neck i.e. level 1-3 from an unknown primary tumor most
likely located in the upper aerodigestive tract. In current diagnostic work-up
comprising PET/CT, panendoscopy and (random) biopsies, 53.4% of these CUPs
remains undetected. In this case, the treatment may consist primarily of
(chemo)radiation or (modified) radical neck dissection followed by adjuvant
radiotherapy of the neck and the possible locations of the unidentified primary
tumor. Recently it was shown that in case of CUP without identification of the
primary tumor, survival increases when a ipsilateral tonsillectomy is
performed. However, accurate identification of the primary tumor is very
important in order to apply optimal treatment. If the primary tumor is
detected, the treatment can be focused on the primary site which improves
therapeutic efficiency and decreases treatment-induced morbidity.
Clearly, new endoscopic *real-time* imaging techniques are needed to visualize
mucosal changes associated with head and neck squamous cell carcinoma and
increase detection rate of the primary tumor. Molecular fluorescence imaging
enables the visualization of targeted tumor-specific biomarkers by using
fluorescence, thereby enhancing the contrast between normal mucosa and tumor
tissue. This could improve the detection of the primary tumor. Narrow band
imaging enhances visualization of changes in vascularization associated with
(pre)malignant lesions. It has been investigated previously with studies
reporting that it is superior to white-light imaging by enabling accentuation
of abnormalities in vasculature of mucosal lesions, however its application in
patients with CUP needs to be further investigated.

This study has been transitioned to CTIS with ID 2024-513897-23-00 check the CTIS register for the current data.

The main objective of this study is to evaluate the use of molecular
fluorescence imaging using cetuximab-IRDye800CW in the detection of the primary
tumor in patients with CUP. In addition, we aim to assess the accuracy of these
imaging modalities in terms of detection rate, sensitivity, specificity,
positive and negative predictive value.

The current study is a non-randomized, non-blinded, prospective, single center,
phase I diagnostic study. 35 patients with CUP will be included. Patients will
be administered with 15 mg or 50 mg cetuximab-IRDye800CW.

Patients will - after written informed consent - receive an intravenous
injection of the fluorescent tracer. Two days later, panendoscopy will be
performed.

Burden
- Time investment: Patients need to visit the UMCG two to four days before
their planned surgery which will take approximately 2 hours. Also, a day before
the planned procedures, patients will receive a laryngoscopy. Usually patients
are admitted on the day of panendoscopy. Therefore the measurements on this day
will not require extra time investment
- Extra procedures: 1) Intravenous administration of cetuximab-IRDye800CW. 2)
The estimated time for taking fluorescence images is approximately 30min.
Therefore the time under general anesthesia will be prolonged. 3) Biopsies will
be taken from suspect areas based on fluorescent or NBI signal.

Risks
Allergic reactions to cetuximab have been reported but this is considered a low
risk. No preclinical or clinical study reported higher than grade 2 adverse
events. In the first study with cetuximab-IRDye800CW, no serious events were
reported in six patients. In an ongoing study at the UMCG at the Department of
Oral and Maxillofacial Surgery, no serious events have been reported.

Benefit
Patients may have benefit from this study directly. The panendoscopy procedure
will be planned as usual. During panendoscopy, biopsies will be taken based on
fluorescence and narrow band imaging. The benefit of this study will be that
identification of the primary tumor by means of this biopsies may lead to a
treatment plan focused on the primary tumor lesion instead of a morbid
treatment of the whole upperaerodigestive tract. Furthermore, the results of
these types of study will be at least beneficial for other patients with cancer
in the future.