Trial Information

Accuracy of Endoscopic Diagnosis of Carcinoma of the UpperAerodigestive Tract: A Tandem Trial of Direct Rigid Endoscopy and Transnasal Flexible Endoscopy With Narrowband Imaging

This is a single arm prospective study to evaluate the concordance between a
standard-of-care diagnostic procedure and TNFE-NBI for diagnosing malignancy. The primary
aim of this investigation is to determine whether the TNFE NBI procedure can detect and
stage cancer in the head and neck as well as the standard DRE which requires general
anesthesia.

Patients who are pending direct laryngoscopy after presenting to the Department of
Otolaryngology-Head and Neck Surgery at UCSF with UADT lesions will be asked to participate
in the study provided all eligibility criteria are met. Under current standard-of-care for
diagnostic evaluation and staging of UADT lesions, patients will undergo imaging studies
including CT and/or MRI of the neck with contrast prior to direct laryngoscopy. Study
participants will undergo both the TNFE NBI and DRE procedures.

The study procedure TNFE NBI will be performed, followed 1-6 weeks later by DRE, the
standard approach for diagnosis, without the surgeon having knowledge of the details of the
first procedure. The sequence of examinations in this investigation is dictated by the need
to minimize mucosal trauma during the first examination and allow for mucosal healing prior
to the second examination, and thus cannot be randomized. TNFE-NBI produces much less
mucosal trauma by avoiding direct blunt manipulation and through the smaller, 1.8mm, cupped
biopsy forceps.

Because it is possible that the TNFE NBI procedure might detect smaller tumors or lesions in
different locations, the biopsy locations from the TNFE NBI procedure will be made known at
the end of the DRE surgery to ensure that all needed areas are biopsied. Therefore, a
secondary aim of this study will be to explore whether the TNFE NBI procedure may improve
the detection of malignancy when added to the DRE surgery.

Patients enrolling in the study will undergo TNFE-NBI with biopsy of suspicious lesions. The
TNFE-NBI examinations will be digitally recorded. The examiner will describe, using standard
language and diagrams, anatomic location of suspicious areas revealed during the procedure.
Biopsy tissue will be labeled as to the area of origin.

In the event that a participant does not tolerate TNFE-NBI, the study procedure will be
aborted.

At least one week and no more than 6 weeks after TNFE-NBI, patients will undergo standard of
care direct rigid endoscopy. The intervening time to DRE is to allow for recovery of
mucosal surfaces.

Participants who did not tolerate TNFE-NBI will undergo DRE as standard of care.

The DRE examiner will be blinded as to which areas were biopsied during the TNFE-NBI
procedure until completion of the standard of care DRE examination and tissue biopsy
selection. In the investigator's experience, areas of prior biopsy will not be apparent to
the DRE examiner as mucosal recovery will occur during 1-6 weeks elapsing between TNFE-NBI
and DRE. Upon completion of the standard of care DRE examination and tissue biopsy
selection, the DRE examiner will open the TNFE-NBI examiner's note describing the areas
deemed suspicious during TNFE-NBI. Additional areas may then be examined and biopsied with
DRE based on the TNFE-NBI note. Records will be kept as to which anatomic areas were:

1. identified by both procedures,

2. identified by DRE only after prompting by the TNFE-NBI note

3. identified by DRE only (not previously identified by TNFE-NBI).

A diagnosis of carcinoma in situ or invasive squamous cell carcinoma will be considered
positive for malignancy. If a diagnosis of malignancy is made after the initial endoscopy,
regardless of which test was positive, the patient will be contacted immediately so that
appropriate treatment can be pursued. For diagnoses of dysplasia and other non-malignant
conditions such as polyp, lymphoid tissue, papilloma, etc., the patient will be scheduled
for follow-up.

Routine follow-up of benign lesions includes a routine head and neck examination, including
indirect laryngoscopy with a fiberoptic endoscope 2-3 months after biopsy. New or enlarging
lesions will be assessed in the operating room with DRE per standard of care. Lesions
initially diagnosed as non-malignant that are stable or not visualized at follow-up will not
need re-biopsy per standard of care.

At the conclusion of study enrollment, all biopsy specimens will be de-identified, batched,
and evaluated by a pathologist blinded to the type of endoscopy. A diagnosis of carcinoma
in situ or invasive squamous cell carcinoma will be considered positive for malignancy.

If patients with non-malignant diagnoses of study pathology (both TNFE-NBI and DRE) have
been diagnosed with malignancy at or before routine follow-up, the study evaluation will be
considered a false negative. If no malignancy developed within three months of the biopsy
procedures, the study evaluation will be considered a true negative. (This design represents
a compromise in evaluating patients with a negative endoscopy. By necessity a negative
diagnosis is one of exclusion, given that complete pathologic evaluation of every patients'
upper aerodigestive tract is neither ethical, practical, nor feasible in clinical practice.
Precedent for this design can be found in Smith-Bindman, Chu et al. 2005)