Comparison of Endoscopic Visualization and CT Imaging of Head and Neck Cancers With Pathological Validation
Conditions: Head and Neck Cancer
Sponsor: University Health Network, Toronto

 
 
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Comparison of Endoscopic Visualization and CT Imaging of Head 
and Neck Cancers with Pathological Validation 
 
UHN REB Protocol Number: TBD 
 
 
Co-Principal Investigators:  
Dr. Robert Weersink, PhD 
Radiation Medicine Program, UHN/PMH 
 
Dr. Jonathan Irish, MD MSc Dept. of Surgical Oncology 
University Health Network and Princess Margaret Hospital (UHN/PMH)  
610 University Avenue,  
Toronto, Ontario  
M5G 2M9 Canada  
 
 
Study Centre:  
University Health Network and Princess Margaret Hospital (UHN/PMH)  
610 University Avenue  
Toronto, Ontario  
M5G 2M9 Canada  
 
 
Co-Investigators:  
 
Dr. John Cho, MD, PhD 
Radiation Medicine Program, UHN/PMH 
Dr. Bayardo Perez-Ordonez, MD 
Dept. of Pathology, UHN/TGH 
 
 
 

 
 
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Version Number: 1.0  
01 March 2017 
STATEMENT OF COMPLIANCE  
The study will be conducted in compliance with the protocol, International Conference on 
Harmonisation [ICH] E6, applicable regulatory requirements, and carried out in accordance with 
Good Clinical Practice (GCP) as per the following:  
• 
Health Canada Health Products and Food Branch [HPFB] Regulations  
• 
Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, Canadian 
Institutes of Health Research, Natural Sciences and Engineering Research Council of 
Canada, Social Sciences and Humanities Research Council of Canada  
• 
Personal Information Protection and Electronic Documents Act, Bill C-6 [PIPEDA]  
• 
USA Food and Drug Administration [FDA] Code of Federal Regulations [CFR] applicable to 
clinical studies (45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312)  
• 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46 
http://www.fda.gov/cder/guidance/959fnl.pdf 
http://www.cancer.gov/clinicaltrials/learning/page3.  
• 
National Institute of Health (NIH) Clinical Terms of Award; 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-061.html  
 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed GCP/Human Subjects Protection Training. 
 
 

 
 
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Name 
Title 
Name 
Title 
Name 
Title 
Name 
Title 
SIGNATURE PAGE  
  
 
The signature below constitutes the approval of this protocol and any attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal, 
regulatory requirements and applicable federal regulations and ICH guidelines.  
 
 
Signed: 
 
 
 
 
 
 
 
Date: 
 
    
 
 
 
 
 
Signed: 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
Signed: 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
Signed: 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 

 
 
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TABLE OF CONTENTS 
 
 
LIST OF ABBREVIATIONS ............................................................................................... 5 
1 
Key Roles ................................................................................................................. 7 
2 
BACKGROUND AND RATIONALE .......................................................................... 8 
3 
Objectives ...............................................................................................................10 
4 
Study Design ...........................................................................................................10 
5 
Study Schema .........................................................................................................12 
6 
Study Enrollment and Withdrawal ............................................................................13 
7 
Study Schedule and Procedures .............................................................................14 
8 
Safety ......................................................................................................................19 
9 
STATISTICAL CONSIDERATION ...........................................................................19 
10 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .........19 
11 
ETHICS/PROTECTION OF HUMAN SUBJECTS ....................................................20 
12 
DATA HANDLING AND RECORD KEEPING ..........................................................22 
13 
References ..............................................................................................................23 
 

 
 
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LIST OF ABBREVIATIONS    
 
AE  
Adverse Event/Adverse Experience  
 
 
CFR  
Code of Federal Regulations  
CIOMS  
Council for International Organizations of Medical Sciences  
 
 
 
 
CRF  
Case Report Form  
CT  
Computerized tomography  
 
 
EM 
Electromagnetic 
FDA  
Food and Drug Administration  
FDG  
Fluoro-deoxyglucose 
GTV 
Gross Tumour Volume 
GTV-endo 
Gross Tumour Volume - Endoscopic 
GTV 
Gross Tumour Volume - Standard 
IGRT 
Image Guided Radiation Therapy 
IMRT 
Intensity Modulated Radiation Therapy 
MRI  
Magnetic resonance imaging 
NIH  
National Institutes of Health  
OAR 
Organ at Risk 
OCI  
Ontario Cancer Institute  
OHRP  
Office for Human Research Protections  
PET  
Positron emission tomography  
PI  
Principal Investigator  
PIPEDA  
Personal Information Protection and Electronic Documentation Act  
PHIPA  
Personal Health Information Protection Act  
PMH  
Princess Margaret Hospital  
REB  
Research Ethics Board  
RMP  
Radiation Medicine Program  
SAE  
Serious Adverse Event/Serious Adverse Experience  
SOP  
Standard Operating Procedure  
STAPLE 
Simultaneous Truth and Performance Level Estimation 
UHN 
University Health Network 
 
 
 
 
 
 
 

 
 
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PROTOCOL SUMMARY 
 
Title  
Comparison of Endoscopic Visualization and CT Imaging of Head 
and Neck Cancers with Pathological Validation 
Population  
• 
Age ≥ 18 years 
• 
Histologic diagnosis of squamous cell carcinoma 
• 
Primary H&N cancer 
• 
Disease visible on endoscopy 
• 
Intention to treat definitively using radical surgery therapy. 
Number of Sites  
One – Princess Margaret Cancer Centre, Toronto, Ontario  
 
Study Duration  
Accrual over 18 months years.  
Description of 
Intervention  
CT imaging immediately prior to surgery. Biopsy sampling of 
tissue samples using tracking and navigation technologies to 
register biopsy sampling to CT images  
Objectives  
Primary Objectives: 
• 
Pathological assessment of superficial extent of disease 
beyond CT-visible disease  
• 
Comparison of Gross Tumour Volume contours to 
pathological findings 
 
Description of Study 
Design  
This is a single centre, single arm feasibility study  
Estimated Time to 
Complete Enrollment:  
10 patients total, over 1.0 years  

 
 
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1 
Key Roles 
 
Principal Investigators  
Dr. Jonathan Irish, MD MSc Dept. of Surgical Oncology 
University Health Network and Princess Margaret Hospital 
(UHN/PMH)  
610 University Avenue,  
Toronto, Ontario  
M5G 2M9 Canada 
Tel: (416) 946-2149 
FAX: (416) 946-2300 
Email: jonathan.irish@uhn.on.ca 
Dr. Robert Weersink, PhD 
Medical Physicist 
Radiation Medicine Program (RMP) 
University 
Health 
Network/Princess 
Margaret 
Hospital 
(UHN/PMH) 
 
Institutional Study Site  
University 
Health 
Network/Princess 
Margaret 
Hospital 
(UHN/PMH) 
610 University Avenue, 
Toronto, Ontario 
M5G 2M9 Canada 
 
Co-investigators  
Dr. John Cho, MD, PhD 
Radiation Oncologist, Radiation Medicine Program (RMP) 
University Health Network/Princess Margaret Cancer Centre 
 
Dr. Bayardo Perez-Ordonez, MD 
Department of Pathology,  
University Health Network/Toronto General Hospital 
 
Dr. Theo van der Kwast, MD 
Department of Pathology,  
University Health Network/Toronto General Hospital 
 
Dr. Jason Wasserman, MD (fellow) 
Department of Pathology, 
University Health Network/Toronto General Hospital 
 
Research Ethics Board 
(REB)  
 
University Health Network, Oncology Research Ethics Board 
Dr. J. Holland, Chair 
700 University Avenue, 10th Floor, 
Toronto, Ontario M5G 1Z5 
Tel. 416-581-7849   Fax: 416-946-2355 
Email : jholland@uhnresearch.ca 

 
 
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2 
BACKGROUND AND RATIONALE 
2.1 Head and Neck Radiotherapy 
Approximately half of cancer patients require radiation therapy (RT)* at some point during their 
care. Technological advances in RT, such as intensity modulation (IMRT) and image guidance 
(IGRT), allow radiation dose delivery with high accuracy and millimeter precision. RT planning 
can be thought of as a serial, step wise chain-like process where each link depends on the 
previous one. As these technical links are improved and strengthened, accurate definition of the 
target is now emerging as the weakest step in the RT process.1 Accurate target definition is 
fundamental to all subsequent treatment planning and delivery and is critical for successful RT. 
Incorrect target definition can result in poorer outcomes through either undercontouring (less 
tumour control), overcontouring (more normal tissue toxicity), and/or both. For head and neck 
(H&N) cancer, the role of various combinations of radiological imaging in target delineation has 
been investigated with respect to target delineation at depth.2-5 However, contouring with only 
standard radiological methods often misses superficial disease when compared to pathological 
sampling.4, 5  
For head and neck cancers, endoscopy is invaluable in visualizing the superficial, 
radiographically occult extent of disease. Relation of these findings to the planning environment, 
however, is based primarily on the treating clinician’s recall of the endoscopically visible disease 
relative to anatomical landmarks, a process subject to substantial contouring bias, error, and 
uncertainty in delineating the target or gross tumour volume (GTV). 
Endoscopic examination of involved endothelial surfaces plays a critical albeit qualitative role in 
target delineation revealing superficial visible tumour extending beyond the invading disease 
apparent on volumetric imaging studies. In current practice, the clinician integrates the 
endoscopic findings into the treatment plan using their clinical judgment, recollection of 
anatomical landmarks and experience to define a target volume. Although clinical practice may 
vary, permanent records of the endoscopic procedure such as screen captures are not typically 
stored in the medical record. The subjectivity of this practice is evident in the large inter-
observer variations observed in most contouring studies that include the physical exam.5, 26 
2.2 Spatially Registered Endoscopy 
To address these issues and improve contouring of superficial disease, we have designed and 
prototyped a novel platform that uses endoscopic tracking and image analysis tools for the 
accurate registration of endoscopic images to the treatment planning CT.12, 13  Disease visible 
on endoscopy can then be contoured and registered to the planning CT, allowing inclusion of 
superficial disease invisible on the volumetric CT image dataset into the treatment plan.  
Specifically, contouring can be performed on 2D endoscopic images, projected into 3D image 
space and imported into the treatment planning software. Our “optical simulation” (or 
endoscopic contouring) technology employs 3 fundamental technologies: an optical imaging 

 
 
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system, tracking technology, and image registration software. These technologies have been 
integrated into a single platform developed primarily for image-guided surgery14, 15 which has 
been used in other REB-approved trials. The optical systems used in our initial studies were 
flexible endoscopes typically used in patient physical exams. Both real and virtual endoscopic 
images can be simultaneously displayed or, using various transparent display techniques can 
be overlaid on each other. Orthogonal views are also displayed showing the camera 
coordinates and contours.  
The endoscopic contouring was demonstrated in pilot clinical studies with accuracies of ~3 mm 
on patients each with early stage (T1) glottic cancer. Endoscopic imaging was performed shortly 
after acquisition of the planning CT images. Patients were examined in the same position as the 
CT imaging, including fixation mask. Video and tracking information was recorded, allowing 
retrospective analysis. The 15 minute procedure was well tolerated by all subjects. Clinicians 
reviewed the video for frames displaying the tumour. Concordance between the endoscopic 
contours and those generated by the CT images alone were excellent along the superficial 
extent of the disease.  
These cases were selected deliberately to be visible on both the optical and CT imaging, 
providing confirmation of contour concordance and as proof of concept. In contrast to this 
protocol, no suspicious submucosal extension was allowed in these patients. The study 
concluded optical simulation was feasible in these patients.  
We currently have a clinical trial examining the impact on contouring accuracy by including 
spatially registered endoscopic imaging to the planning CT. Despite limited enrollment, several 
of the cases have shown large discrepancies between the CT visible GTV and the GTV 
contoured when endoscopic information is included. 
The proposed study will examine the necessity of endoscopic contouring by comparison with 
pathology in a limited number of patients with oral cancer that are scheduled for surgical 
resection. Using image-guided surgery tools very similar to those used in the endoscopic 
contouring, we will compare GTV delineation of H&N cancers with and without the use of 
endoscopic contouring to pathologic findings. The study will use resources available in the GTx-
OR (described below) to perform endoscopic contouring on oral cancer patients during the 
surgical procedure, immediately prior to resection.  
The resected samples will be processed using whole mount pathology methods. Images of the 
whole mount tissue sections will be registered with the CT images acquired before and during 
surgery so that the pathology findings can be spatially correlated with the CT and endoscopic 
imaging. The pathology findings will also aid in defining the superficial extent of the disease and 
if these findings correlate with the region defined by the endoscopic imaging. 
 

 
 
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3 
Objectives 
3.1 Primary Objectives 
3.1.1 To compare the location of lesions visible on the tissue surface with standard CT 
imaging and pathology 
3.2 Secondary Objectives 
3.2.1 To determine the registration accuracy of spatially navigated endoscopy in a 
controlled surgical setting.  
4 
Study Design 
4.1 Overview 
4.1.1 This is a single centre, single arm feasibility study comparing target delineation of 
GTV for H&N cancer to pathology using either standard CT-based contouring or 
spatially registered endoscopy combined with CT-based contouring. 
4.1.2 Oral cancer surgery will be performed under image-guidance, including a 
standard contrast-enhanced CT scan immediately prior to the resection 
procedure. This CT scan will replicate the standard radiation planning CT scan 
and will be used for delineation of the GTV-std. External fiducial markers will be 
placed on the patient for registration of the navigation tools to the CT image 
coordinate system. 
4.1.3 During surgery, the superficial lesion will be mapped using either a standard 
pointing tool that will be used by the surgeon to outline the lesion or navigated 
endoscopy will be performed of the superficial disease visible in the oral cavity. 
The endoscopic video will be spatially registered to the prior CT scan and used 
post-procedure for endoscopic contouring as an aid in delineation of the GTV.  
4.1.4 The tissue will be marked along all planned excisions and resected using 
standard protocols. The surgical specimen will be mounted and scanned fresh in 
the OR using the CT scanner and a small animal MRI for correlative pathology. 
The sample will be prepared for whole mount pathology mapping by embedding 
the fixed tissue in a gel. The sample will be imaged again using the small animal 
MRI. It will then be delivered to pathology whole-mount section and identification 
of disease margins, both superficial and at depth. Details of the pathology 
workflow are in Section 7.6. 
4.1.5 Following the procedure, contouring of the GTV will be performed by a radiation 
oncologist unfamiliar with the surgery and using only the CT image. The mapping 

 
 
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of the superficial lesion (from 4.1.3) will be added to the CT image and the errors 
between the standard CT-based contouring and the extent of the superficial 
lesion will be measured. The standard contours and lesion mapping will be 
compared to pathology for concordance and volume. 
4.2 Integration with Standard Treatment of H&N Cancer 
4.2.1 The patient will undergo standard clinical assessment and preparation for 
surgical resection of oral lesions.  
4.2.2 A standard contrast-enhanced CT scan will be added to the standard surgical 
procedure, with fiducial markers placed on the patient’s skin and with the patient 
in same position as used during surgery. 
4.2.3 During the surgery, the superficial disease will be delineated using either a 
pointing tools tracking the outline of the tumour or using navigated endoscopy. 
The delineated disease will be registered to the initial CT scan using fiducial 
markers placed on the patient prior to the CT scan.  
4.2.4 Patients will receive standard treatment for oral H&N cancer with surgery 
according to the UHN H&N oncology site policies. Treatment will not be modified 
based on the results of this study.  
4.2.5 The radiation oncologist(s) will use the intra-operative CT scan to delineate the 
GTV as per standard clinical practice.  
4.2.6 The overlap and differences between the mapped superficial disease and the 
GTV will be measured.  
4.2.7 The locations of the disease identified by the CT scanning and the superficial 
lesion mapping will be correlated with the pathology reports. (See Sections 7.2 
and 7.6 below for details) 
 
4.3 Integration with Other Studies in Patients with H&N Cancer 
4.3.1 Patients who participate in this study will be also be eligible to participate in other 
biomarker or therapeutic studies aimed at better characterizing the biologic 
behavior of H&N cancer or improving clinical outcome. Patients will be consented 
separately for these other studies.  

 
 
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5 Study Schema 
Tasks highlighted in grey are additional steps not part of standard clinical practice. 
Target Population 
• Age ≥ 18 years 
• Histologic diagnosis of squamous cell carcinoma of the H&N 
• Primary cancer of H&N  
• Ability to provide written informed consent to participate in the study 
Obtain Informed Consent 
Preparation for Surgery in GTx OR 
Contrast-enhanced CT with extra fiducial markers on patient. Patient positioned in 
surgical position with fixation if necessary/possible. 
Patient transfer to OR table  
Registration of tracking equipment to CT using fiducial markers on patient.  
Retrospective identification of video frames by oncologists to be used for 
contouring. Contouring of GTV-endo on chosen endoscopic video frames. 
Registration of GTV-endo to planning CT 
Intra-OR Imaging of resected sample 
Surgery completed as per standard procedures. 
Evaluation of contours comparing GTV and superficial lesion mapping to pathology 
Patient positioning and anesthesia 
Surgical excision completed including marking of margins for pathology.  
Pathology reporting spatially correlated with imaging 
Pathological sampling using navigated core biopsy registered to CT 
Mapping of superficial disease using either a) pointing tool or b) navigated 
endoscopy. Choice determined by surgeon. 
Standard Pathology Processing 

 
 
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6 
Study Enrollment and Withdrawal 
6.1 Inclusion Criteria 
Patients will be eligible for inclusion in this study if they meet all of the following criteria: 
6.1.1 
Age ≥ 18 years 
6.1.2 
Histologic diagnosis of oral squamous cell carcinoma  
6.1.3 
Primary cancer of the H&N  
6.1.4 
Intention to treat using surgery. 
6.1.5 
Ability to provide written informed consent to participate in the study 
6.2 Exclusion Criteria 
6.2.1 
Prior complete or partial radiation therapy to H&N 
6.2.2 
Prior complete or partial surgery of the tumour 
6.2.3 
Concurrent illness or condition that precludes subject from undergoing 
endoscopy or CT scanning 
6.2.4 
Psychiatric or addictive disorders that preclude informed consent or adherence 
to protocol 
6.3 Criteria for Withdrawal 
6.3.1 
Subject requests withdrawal from study for any reason 

 
 
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7 
Study Schedule and Procedures 
7.1 Clinical Evaluation and Informed Consent 
7.1.1 Eligible patients are required to provide written, informed consent prior to study 
participation. 
7.1.2 The start of treatment for H&N cancer will not be delayed by participating in this 
study. Surgery will proceed as schedule. 
7.2 Design & Methodology 
7.2.1 Using the Somatom FLASH CT scanner in the OR, a contrast-enhanced CT scan 
using standard Radiation Medicine protocols will be performed minus the use of 
a head fixation mask. The contrast agent will be Visipaque. The patient will be 
awake and generally positioned as they would be for the surgery/endoscopy 
procedure. Fiducial markers will be added to the patient’s surface to be used for 
the registration of the endoscopy to the CT imaging.  
7.2.2 The patient will be transferred to the operating table that is part of the ZEEGO 
robotic imaging device. In this transfer, the Zeego table is rotated and extended 
so that it aligns with the table of the CT scanner tables. A thin carbon fiber board 
under the patient is lifted and the patient moved to the Zeego table. A similar 
procedure has been used in other protocols in the GTx OR. 
7.2.3 Patient is prepared for surgery. 
7.2.4 Prior to tumour excision, surgeon defines the observable superficial extent of the 
disease one of two methods, determined at the discretion of the surgeon. One 
option uses a tracked pointing tool to record its position as the surgeon moves 
the pointer around the outline of the superficial disease. The other option is to 
use navigated endoscopy to record video of the superficial disease. (See Section 
7.5) The endoscopes used here can be either rigid (with optical tracking) or 
flexible (using EM tracking) 
7.2.5 The surgical procedure will continue using standard of care. Immediately prior to 
resection of the visible tumour, the tissue will be marked to identify visible extent 
of the superficial disease and the added margin. The navigated endoscopy will 
be repeated so that it includes these markings. 
7.2.6 After surgical resection, a cone-beam CT scan will be acquired to define the 
location of the resected tissue. The cone-beam CT scan will be registered to the 
pre-resection CT scan for comparison of the resected volume and the disease 
contoured by the radiation oncologists. (See 7.2.9 below). 

 
 
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7.2.7 The resected tissue sample will be imaged again using a small field of view MRI 
scanner (0.5T) located in the OR. The tissue sample will then be sent to 
pathology for standard assessment. See Section 7.6 below for details of 
pathology handling. 
7.2.8 Following the surgical procedure, the pre-operative CT scan will be evaluated by 
3 observers. Each will independently perform contouring of the GTV. These 
observers will be practicing radiation oncologists at Princess Margaret Cancer 
Centre.  
7.2.9 The shape and position of the superficial lesion defined by the tool tracking or 
navigated endoscopy (7.2.4) will be registered to the CT scan. 
7.2.10  Pathology reporting will be correlated to the CT image set, allowing for 
measurements of the correspondence between the pathology and the contouring 
of the disease using the CT scan and the superficial disease. 
7.3 Intraoperative CT Scanning 
7.3.1 The CT scan will be an additional scan of the patient beyond standard of care. 
The typical dose for a CT scan of the head is 2-3 mSv. This is similar to the 
annual background radiation exposure in Canada. The contrast agent is Health 
Canada approved. 
7.4 Equipment and Software for Endoscopic Contouring 
7.4.1 The navigation tools and image guidance software platform used in this protocol 
have been developed within UHN. The tools include real-time optical and 
electromagnetic tracking (using commercially available equipment from NDI, 
Waterloo, ON) of surgical instruments and endoscopes co-registered to CT and 
MR imaging and display of the imaging information using augmented 
visualization methods. The necessary functions include:  
• 
reading of CT images and data,  
• 
tracking of EM sensors, calibration of endoscopic images,  
• 
registration of CT image and EM coordinate spaces,  
• 
registration of video images to CT images,  
• 
selection of video frames for contouring,  
• 
contouring on endoscopic images and  

 
 
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• 
export of endoscopic contours for reading by the treatment planning 
system.  
7.4.2 This package has been demonstrated in several previous and current REB 
protocols:  
UHN REB 11-0660-CE, Localized Intraoperative Virtual Endoscopy (LIVE) for Surgical 
Guidance in Sinus and Skull Base Patients 
UHN REB 12-5315: The Translational Research Image-Guided Operating Room 
(TRIGORA): Intraoperative 3D Imaging for Head & Neck Surgical Patients 
UHN REB 13-5914-C: Comparing Target Delineation of Head and Neck Cancers With 
and Without the Aid of Spatially Registered Endoscopy 
UHN REB 15-9147-CE: Intraoperative 3D Imaging and Navigation for Patients with 
Benign Bone Tumours 
7.5 Endoscopy Procedures 
7.5.1 The endoscopy procedure will follow the CT scan and patient transport, which 
will be within 30-40 minutes following the CT scan. If necessary, immobilization 
devices may be used to fix the patient in the same position for endoscopy as 
used during the CT scan. Small plastic fiducial markers will be temporarily added 
to the patient using double sides tape. Once the patient is in place on the surgical 
table, CT to EM registration will be performed. The fiducial markers placed on the 
patient will be identified and located in both the CT image and in real space using 
the EM secondary pointing tool.   
7.6 Pathology Correlation Procedures 
Specifics of tissue handling: 
Notification of a case pathologist (Drs. Bayardo Perez-Ordonez or Doaa AlGhamdi) and 
Surgical Pathology Laboratory Grossing room at UHN by Dr. Irish of name, MRN and 
date of surgery of patient scheduled for oral/tongue resection. 
2.      Sample taken by GTx staff to Pathology on 2nd floor TGH. Accessioning of surgical 
specimen by technologist upon arrival from OR and verification of the specimen by case 
pathologist. . Inform biobank personnel that the case may not be biobanked. 
3.      Fresh sample taken by GTx staff to small animal MRI on 7th floor Princess Margaret 
Discovery Tower (PMDT). T2-weighted (T2) and T1-weighted imaging of fresh sample 
within 2 hours of surgery. 

 
 
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4.      Sample returned by GTx staff to Pathology on 2nd floor TGH. No incisions in the specimen 
are allowed to preserve the anatomy. Fixation and processing of the surgical specimen 
with neutral buffered formalin then overnight fixation of the specimen immersed in 
formalin. This may include injection of formalin into the specimen. 
5.      Gross description, including inspection orientation and measuring of the specimen and 
inking (with multiple colors to determine margin status and to aid in orientation) according 
to standard operating procedure. Recording of data on a requisition sheet.  
6.      Removal of stitches and/or sutures of specimen by Head and Neck 
pathologists/pathology fellow.   
7.      Gel embedding of sample, including MR visible markers to aid in identifying slice location. 
Once complete, fixed sample taken by GTx staff to small animal MRI on 7th floor PMDT 
for T2 and T1-weighted imaging.  
8.      Sample returned by GTx staff to Pathology on 2nd floor TGH. Sectioning at a 3mm interval 
will be done by a head and neck pathologist/fellow. Gross digital pictures of each section 
will be taken.  Sections will then be sent for paraffin infiltration by UHN pathology. 
9.      Histologic wholemount processing (further sectioning to 4-6μm thickness, mounting of 
sections on slides, staining with hematoxylin and eosin (H&E) stain).  Each paraffin bock 
and slide will contain a label that includes the accession number and a number for 
identification of a section.  
10.   Return of stained sections to UHN pathology.  An e-mail of acknowledgement of receipt 
will be sent to Dr. Irish and Dr. Weersink by the receiving pathologist.  Slides will be 
taken by GTx staff to Advanced Optical Microscopy Facility on 15th floor PMDT and 
scanned at histologic resolution (20x) with an Aperio scanner.      
11.   Outlining of malignant and ablated areas of surgical section in marker to be completed by 
the head and neck pathologist. The marked histologic slides will then be digitized and 
reconstructed into whole mount sections. Slides with outlined tumours will be digitized 
using a flat-bed scanner at 300dpi.  
12.   All cancerous regions marked and contoured on pathology will be registered on the 
corresponding parametric maps from each MRI data set. The MRI data will be registered 
to the post-resection cone-beam CT scan and the original planning CT image. This will 
register the pathological contours with those contoured by the radiation oncologists in 
step 7.2.9.  
 
7.7 Metrics 
7.7.1 
Analysis will correlate the pathological sampling to the imaging. Specifically, we 
will compare the number of samples that show superficial disease and how this 
matches the location of the GTV as determined by CT imaging alone (GTV-std) 

 
 
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and the location of the GTV as determined by the combination of CT imaging and 
navigated endoscopy (GTV-endo). 
7.7.2 
Analysis will correlate the pathological sampling to the imaging. Specifically, we 
will measure the overlap of the pathology with the tumour defined using CT 
imaging alone, and the overlap of the pathology with the mapping of the 
superficial extent of the disease determined during surgery using either the 
pointing tool or navigated endoscopy. 
7.7.3 
Concordance of GTV-std and GTV-endo using conformity indices22 such as 
DICE23, or STAPLE.24 These metrics estimate the differences between the GTV 
contours.  
7.8 Data Collection 
For each patient, a single anonymized identifier will be used. The following data will be 
collected: 
• 
Date of surgery 
• 
Tumour site 
• 
Tumour type 
• 
CT images (from 7.2.1) 
• 
Intraoperative cone beam CT (from 7.3.1) 
• 
Endoscopic video (from 7.5.1) 
• 
Pathology data, including whole mount images (7.6) and tumour classification from 
pathology reports 
A data collection summary sheet will be stored for each patient. 
 
 

 
 
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8 
Safety 
8.1 CT Scan 
8.1.1 An additional contrast-enhanced CT scan will be required. The additional dose to 
the patient resulting from this scan is minor. The routine CT Head & Neck scan 
conducted as standard of care at UHN delivers ionizing radiation of 3.0-5.0 mSv 
to the patient.  For comparison, this exposure is equivalent to about one year of 
background radiation exposure from living in North America (2.0 - 3.0 mSv), 
while for people living on the plateaus of Colorado or New Mexico, the annual 
background radiation exposure is 3.5 - 4.5 mSv.  REB 11-0192-C was granted to 
image a very similar patient population to the present study, with similar 
demographics and the same diagnosis. 
9 
STATISTICAL CONSIDERATION 
9.1 Sample Size 
9.1.1 This study will accrue up to 10 patients with H&N cancer, leading to 10 whole 
mount pathology samples in total. The reporting of the pathology findings will be 
spatially correlated to the imaging. If possible, other pathological findings will be 
used in the analysis if sufficient spatial correlation can be recovered based on 
tissue markings used with the excision. 
9.1.2 The number of H&N oral cancer cases that proceed to surgery is ~5 per week, 
Assuming an accrual of 10%, this would average approximately 1-2 cases per 
month.   
10 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
Appropriate documentation will be maintained for this trial, in compliance with ICH E6, Section 
4.9 and OCI/PMH institutional requirements for the protection of confidentiality of subjects. The 
documentation will be stored for a period of 25 years in accordance with Health Canada 
Regulations.  
Only designated personnel will have access to records. Only authorized representatives of the 
sponsor or regulatory agencies will be allowed to examine (and when required by applicable 
law, to copy) clinical records for the purposes of quality assurance reviews, audits, or evaluation 
of the study safety and progress.  

 
 
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11 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
11.1 Ethical Standard 
The PI will ensure that this study is conducted in full conformity with the principles set forth in 
the Declaration of Helsinki, CIOMS, International Ethical Guidelines for Biomedical Research 
Involving Human Subjects (2002), The Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Subjects of Research of the US National Commission for the Protection of 
Human Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 
CFR Part 46 and/or the ICH E6; 62 Federal Regulations 25691 (1997). 
 
11.2 Institutional Review Board 
The institution must provide for the review and approval of this protocol and the associated 
informed consent documents, and relevant recruitment material by an appropriate independent 
research ethics board [REB]. Any amendments to the protocol or informed consent materials 
must also be approved before they are placed into use. 
 
11.3 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continuing throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and their families. 
Consent forms, separate from the protocol document, describing in detail the study 
interventions/products, study procedures, and risks are given to the subject and written 
documentation of informed consent is required prior to starting intervention/administering study 
product (see Appendix for sample of Informed Consent Form). Consent forms will be REB-
approved and the subject will be asked to read and review the document. Approved consent 
forms may be available translated into other languages, as applicable. 
Upon reviewing the document, the investigator will explain the research study to the subject and 
answer any questions that may arise. The subjects will sign the informed consent document 
prior to any procedures being done specifically for the study. The subjects should have the 
opportunity to discuss the study with their surrogates or think about it prior to agreeing to 
participate. The subjects may withdraw consent at any time throughout the course of the trial. A 
copy of the informed consent document will be given to the subjects for their records. The 
privacy, rights and welfare of the subjects will be protected by emphasizing, to them, that the 
quality of their medical care will not be adversely affected if they decline to participate in this 
study. 
 

 
 
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11.4 Subject Confidentiality  
Subject confidentiality will be strictly held in trust by the participating investigators, their staff, 
and the sponsor and their agents, and will be in compliance with the Personal Health 
Information Protection Act (PHIPA) and other applicable legislation.  
All study related documentation, data, and all other information will be held in strict confidence 
in accordance with the Personal Information Protection and Electronic Documentation Act 
(PIPEDA) and other applicable regulation.  
Authorized representatives may inspect all documents and records required to be maintained by 
the investigator, including but not limited to, medical records (office, clinic, or hospital) and other 
relevant records for the subjects in this study. 
In the event of personal information disclosure to an unauthorized party, any further release of 
information will be stopped, as much information as possible will be retrieved, UHN REB and 
UHN Privacy Office will be contacted, and then further actions will be taken based on their 
recommendations.   
 
 

 
 
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12 
DATA HANDLING AND RECORD KEEPING  
The PI is responsible to ensure the accuracy, completeness, legibility, and timeliness of the data 
reported. All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data.  
12.1 Data Management Responsibilities  
All source documents must be reviewed by the clinical team and data entry staff, who will 
ensure that they are accurate and complete. Adverse events must be graded, assessed for 
severity and causality, and reviewed by the site PI or medical designate.  
Data collection is the responsibility of the clinical research staff at the site under the supervision 
of the site PI. During the study, the investigator must maintain complete and accurate 
documentation for the study.  
12.2 Study Records Retention  
As per Health Canada regulations, study documents will be retained for a minimum of 25 years. 
No clinical trial records will be destroyed without the written consent of the sponsor and PI, if 
applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained.  
12.3 Protocol Deviations  
The site PI and study staff are responsible for knowing and adhering to the study protocol and to 
the reporting requirements of relevant regularity agencies (e.g. UHN REB, Health Canada as 
applicable). A protocol deviation is any noncompliance with the clinical trial protocol, Good 
Clinical Practice (GCP), The noncompliance may be either on the part of the subject, the 
investigator, or the study site staff. All deviations from the protocol must be addressed in study 
subject source documents. As a result of deviations, corrective actions are to be developed by 
the site and implemented promptly. These practices are consistent with ICH E6.   

 
 
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13 
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