Evaluation of the Role of Tongue Base MucOsectomy and Step sErial Sectioning in the Management of the Unknown Primary Squamous Cell Cancer in the Head and Neck
Conditions: Squamous Cell Carcinoma of the Oropharynx
Sponsor: Royal Marsden NHS Foundation Trust

Page 1 
THE MOSES STUDY 
 
Evaluation of the role of tongue base MucOsectomy and 
Step sErial Sectioning in the management of the unknown 
primary squamous cell cancer in the head and neck 
 
Protocol version:
Protocol version:
Protocol version:
Protocol version: 
V4.2
Date:
Date:
Date:
Date: 
18 March 2022
 
Sponsor:
Sponsor:
Sponsor:
Sponsor:  
The Royal Marsden NHS Foundation Trust
 
Fulham Road, London SW3 6JJ, United Kingdom
 
CCR number:
CCR number:
CCR number:
CCR number: 
CCR5065
IRAS number:
IRAS number:
IRAS number:
IRAS number: 
256047
 
Funders: 
Funders: 
Funders: 
Funders:  
Oracle Cancer Trust: GAL_RMH131218
 
Biomedical Research Centre: W94505-B062
 
Chief Investigator:
Chief Investigator:
Chief Investigator:
Chief Investigator: 
Professor Vinidh Paleri
 
Consultant Head & Neck and Thyroid Surgeon,
 
The Royal Marsden Hospital, London
 
Professor of Robotic & Endoscopic Head & Neck Surgery,
 
The Institute of Cancer Research, London
 
Clinical Research 
Clinical Research 
Clinical Research 
Clinical Research  
Fellow:
Fellow:
Fellow:
Fellow: 
Mr John Hardman 
The Institute of Cancer Research, London 
Specialty Registrar in Otorhinolaryngology, 
The Royal Marsden Hospital, London 
 
Pathologist:
Pathologist:
Pathologist:
Pathologist: 
Dr Max Robinson
 
Senior Lecturer in Oral Pathology
 
School of Dental Sciences at Newcastle University
 
Honorary Consultant Pathologist
 
Newcastle upon Tyne Hospitals NHS Foundation Trust
 
Molecular analysis:
Molecular analysis:
Molecular analysis:
Molecular analysis: 
Dr Ben O’Leary
NIHR Clinical Lecturer 
   The Institute of Cancer Research, London 
   The Royal Marsden Hospital, London 
 
Contact:
Contact:
Contact:
Contact: 
moses.study@rmh.nhs.uk
This protocol follows the format recommended by WHO found at “Recommended format for a Research Protocol” 
found at http://www.who.int/rpc/research_ethics/format_rp/en/ and the template provided by the Health 
Research Authority at https://www.hra.nhs.uk/planning-and-improving-research/research-planning/protocol/. 

MOSES Protocol v4.2 
 
 18 March 2022 
IRAS: 256047 
CCR: CCR5065 
Page 2 
Table of contents  
 
1 
Version history ................................................................................................................... 3 
2 
Table of acronyms .............................................................................................................. 4 
3 
Project summary ................................................................................................................ 5 
4 
Signature page.................................................................................................................... 6 
5 
Rationale & background information ................................................................................. 7 
6 
Study aim and objectives .................................................................................................... 8 
7 
Study design and setting .................................................................................................... 9 
8 
Patient eligibility criteria................................................................................................... 10 
9 
Study procedure and methodology .................................................................................. 11 
10 Assessment timings .......................................................................................................... 16 
11 Data management ............................................................................................................ 18 
12 Statistics and data analysis ............................................................................................... 19 
13 Problems Anticipated ....................................................................................................... 23 
14 Project Management ........................................................................................................ 24 
15 Ethical considerations ...................................................................................................... 25 
16 Informed consent process ................................................................................................ 26 
17 Budget .............................................................................................................................. 27 
18 Collaboration with other scientists or research institutions ............................................ 28 
19 Financing and Insurance ................................................................................................... 29 
20 References ........................................................................................................................ 30 

MOSES Protocol v4.2 
 
 18 March 2022 
IRAS: 256047 
CCR: CCR5065 
Page 3 
1 Version history 
Version
Version
Version
Version 
Date
Date
Date
Date 
Version
Version
Version
Version 
0.1
9/1/19
Sponsor application
1.0
5/4/19
Amendments following CCR review
1.1
9/7/19
Amendments following REC review
2.0
3/10/19
Update of database management procedures
2.2
1/7/20
CRF and consent clarifications following COVID-19
2.3
26/10/20
Addition of anonymised histology reports
3.0
03/06/21
Clarification to recruitment target, amendment to 
inclusion/exclusion criteria 
3.1
10/09/21
TBM Sample Recruitment period updated
4.1
01/10/21
Extend recruitment target, recruitment period, follow-up 
duration, and molecular analysis 
4.2
18/03/22
Updated sample shipment details

MOSES Protocol v4.2 
 
 18 March 2022 
IRAS: 256047 
CCR: CCR5065 
Page 4 
2 Table of acronyms 
Acronym
Acronym
Acronym
Acronym 
Meaning
Meaning
Meaning
Meaning 
CCR
Committee for clinical research
CH
Conventional histology
CRF
Case report form
CT
Computed tomography
CUP
Cancer of unknown primary
EBV
Epstein Barr virus
FNAC
Fine needle aspiration cytology
GCP
Good clinical practice
H&E
Haematoxylin and eosin stain
H&N
Head and neck
HNC
Head and neck cancer
HNSCCUP
Head and neck squamous cell carcinoma of unknown primary
HPV
Human papilloma virus
ICF
Informed consent form
IRAS
Integrated research application system
MDADI
M. D. Anderson Dysphagia Inventory
MDT
Multidisciplinary team
MRI
Magnetic resonance imaging
MTA
Material Transfer Agreement (Part of HRA Statement of Activities)
PET CT
Positron emission tomography and computed tomography
PIS
Participant information sheet
REC
Research ethics committee
RMH
Royal Marsden Hospital
RVI
Royal Victoria Infirmary, Newcastle (laboratories)
SAE
Stamped addressed envelope
SCC
Squamous cell carcinoma
SOP
Standard operating protocol
SSS
Step serial sectioning
TBM
Tongue base mucosectomy

MOSES Protocol v4.2 
 
 18 March 2022 
IRAS: 256047 
CCR: CCR5065 
Page 5 
3 Project summary 
Study 
Study 
Study 
Study title
itle
itle
itle
Evaluation of the role of tongue base MucOsectomy and Step sErial Sectioning in 
the management of the unknown primary squamous cell cancer in the head and 
neck. 
Short 
Short 
Short 
Short title
itle
itle
itle 
The MOSES Study.
Study 
Study 
Study 
Study design
esign
esign
esign 
Multicentre prospective observational cohort study, incorporating 
histopathological and molecular tissue analysis. 
Study setting
Study setting
Study setting
Study setting 
UK centres performing TBM to for suspected HNSCCUP.
Study 
Study 
Study 
Study participants
articipants
articipants
articipants 
Patients with suspected head and neck squamous cell carcinoma of unknown 
primary (HNSCCUP) undergoing tongue base mucosectomy (TBM). 
Planned 
Planned 
Planned 
Planned sample 
ample 
ample 
ample size
ize
ize
ize 
100.
Follow
Follow
Follow
Follow-up duration
up duration
up duration
up duration 
5 years.
Planned study period
Planned study period
Planned study period
Planned study period 
Until recruitment of planned sample size.
Aim
Aim
Aim
Aim 
To understand the current management of suspected HNSCCUP patients 
undergoing TBM in the UK, including adequacy of current histology, functional 
and oncological outcomes, and disease biology.  
Objectives
Objectives
Objectives
Objectives 
Primary: 
• 
To establish if step serial sectioning (SSS), compared to conventional 
histology, improves identification of a primary site in TBM and tonsil 
specimens in suspected HNSCCUP. 
Secondary: 
• 
To compare the pick-up rate of primary cancers in TBM specimens 
between surgical methods (robotic vs laser vs endoscopic). 
• 
To prospectively evaluate swallowing function and pain scores after 
TBM. 
• 
To understand patient views and experiences of undergoing TBM for 
suspected HNSCCUP. 
• 
To report time-to-event data for local, regional and distant disease 
recurrence, and mortality. 
• 
To assess the molecular makeup of patients with suspected HNSCCUP 
undergoing TBM. 
Methods
Methods
Methods
Methods
• 
Identification of patients prior to TBM surgery. 
• 
Step serial sectioning histology performed on tongue base and tonsil 
tissue (if available) to compare to conventional histology results. 
• 
Functional follow-up using patient completed questionnaires for pain 
and swallowing function (MDADI) at baseline and intervals up to 5 years. 
• 
Clinical oncological follow-up recorded for up to 5 years. 
• 
Exploratory molecular analysis of tongue base, tonsil (if available) and 
cervical metastatic tissues. 
Expected outcomes
Expected outcomes
Expected outcomes
Expected outcomes 
• 
Increased identification of single and multi-focal primary cancers on SSS. 
• 
Reasonable recovery of functional outcomes after TBM surgery prior to 
administration of radiation therapy.  
• 
Acceptance of TBM and SSS amongst suspected HNSCCUP patients. 
• 
Greater understanding of the molecular make-up of suspected 
HNSCCUP. 

MOSES Protocol v4.2 
 
 18 March 2022 
IRAS: 256047 
CCR: CCR5065 
Page 6 
4 Signature page 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the study in compliance with the approved protocol and will adhere to 
the principles outlined in the Declaration of Helsinki, the Sponsor’s SOPs, and other regulatory 
requirement. 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the investigation without the prior written 
consent of the Sponsor 
I also confirm that I will make the findings of the study publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the study will be given; and that any discrepancies from the study as planned in this protocol 
will be explained. 
 
For and on behalf of the Study Sponsor:
 
 
Print Name
Print Name
Print Name
Print Name: 
 
 
 
Signature: 
Signature: 
Signature: 
Signature:  
  
 
 
Date: 
Date: 
Date: 
Date:  
 
Chief Investigator: 
 
 
Print Name
Print Name
Print Name
Print Name: 
Vinidh Paleri
Vinidh Paleri
Vinidh Paleri
Vinidh Paleri 
 
 
Signature: 
Signature: 
Signature: 
Signature:  
 
 
Date: 
Date: 
Date: 
Date:  
 
 
 

MOSES Protocol v4.2 
 
 18 March 2022 
IRAS: 256047 
CCR: CCR5065 
Page 7 
5 Rationale & background information 
Approximately 5% of head and neck cancer (HNC) present with a neck metastasis with no clinically 
evident primary site.[1,2] Patients undergo clinical examination and cross-sectional imaging to attempt 
to identify this primary site.[3] If the origin of the cancer is still not apparent, then FDG PET combined 
with CT can be used. A proportion of these patients will still not have their primary cancer identified. In 
these instances, patients would have traditionally undergone a panendoscopy including bilateral 
tonsillectomy and random biopsies, including of the tongue base. More recently, a surgical procedure 
called tongue base mucosectomy (TBM) has been used to remove all the mucosa and lymphoid tissue 
from the back of the tongue in an attempt to improve on the low diagnostic yield seen in random 
tongue base biopsies.[4] 
Currently, treatment strategies for CUP in H&N are not standardised. Management plans can vary from 
no radiation therapy addressing potential primary sites, with a watch and wait policy, to Elective 
Mucosal Irradiation (EMI) which can lead to significant early and late morbidity. Identification of the 
primary site has a number of potential advantages. The primary site may be completely excised with an 
adequate margin, in which case it may be suitable for single modality therapy. There may also be a 
significant negative psychological burden if the primary cancer has not been identified or addressed. 
Conversely, a positive margin in the resected specimen could indicate escalated therapy, with 
concomitant chemotherapy, if it felt to be inadequately excised (the procedure is diagnostic not 
oncological). Further, the identification of multicentric primary sites may also lead to an increased 
radiation field compared to if this added information were not available. The benefit of TBM is, as such, 
yet to be fully established.[4,5] 
Human papilloma virus (HPV) is thought to play a significant role in many of these cancers presenting 
as CUP.[6,7] Smaller or involuted primary foci are known to be more common in HPV related cancers 
which may be contributing to the apparent incidence of these unknown primaries, or occultomas as 
they may also be called. A histological technique called step serial sectioning (SSS) allows examination 
of tissue specimens in greater detail than conventional histology. It has not previously been used to 
investigate the primary site in head and neck cancer but the oropharyngeal tissues that potentially 
harbour these small primaries make a sensible target to pioneer its usage. It is hypothesised that 
utilising SSS on tonsillectomy and TBM specimens may increase the identification rate of the primary 
site and may subsequently affect recommended management.  
Currently, we do not understand why some cancers present with cervical metastases with no evident 
primary site. There has been an explosion in genomics research in many cancers, but this remains an 
understudied area in head and neck cancer. There are currently no treatments available to patients 
with head and neck cancer based on genomic insights. This study aims to begin to address the unmet 
need of patients who present with these poorly understood cancers and to provide a starting point for 
more detailed investigations into the relationships between cancer genomics and clinical outcomes. 
 

MOSES Protocol v4.2 
 
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IRAS: 256047 
CCR: CCR5065 
Page 8 
6 Study aim and objectives 
6.1 Aim: 
To understand the current management of suspected HNSCCUP patients undergoing TBM in the UK, 
including adequacy of current histology, functional and oncological outcomes, and disease biology. 
6.2 Primary objective:  
• 
To establish if step serial sectioning (SSS), compared to conventional histology, improves 
identification of a primary site in TBM and tonsil specimens in suspected HNSCCUP. 
6.3 Secondary objectives: 
1. To compare the pick-up rate of primary cancers in TBM specimens between surgical methods 
(robotic vs laser vs endoscopic). 
2. To prospectively evaluate swallowing function and pain scores after TBM. 
3. To understand patient views and experiences of undergoing TBM for suspected HNSCCUP. 
4. To report time-to-event data for local, regional and distant disease recurrence, and mortality. 
5. To assess the molecular makeup of patients with suspected HNSCCUP undergoing TBM. 
 
 

MOSES Protocol v4.2 
 
 18 March 2022 
IRAS: 256047 
CCR: CCR5065 
Page 9 
7 Study design and setting 
7.1 Study design 
Multicentre prospective observational cohort study, incorporating histopathological and molecular 
tissue analysis.  
[Qualitative descriptive study with thematic analysis]. 
7.2 Study setting 
UK centres performing TBM to for suspected HNSCCUP. 

MOSES Protocol v4.2 
 
 18 March 2022 
IRAS: 256047 
CCR: CCR5065 
Page 10 
8 Patient eligibility criteria 
8.1 Population 
Suspected HNSCCUP patients, with a diagnosis of squamous cell cancer from cervical lymph node 
biopsy, with the primary disease presumed to be of head and neck origin, who have not had the primary 
site identified by either clinical examination or cross-sectional imaging (CT/MRI) including PET CT. 
8.2 Inclusion criteria 
• 
Aged 16 or over 
• 
Both sexes  
• 
Cervical metastatic SCC, confirmed with cytology or biopsy, undergoing TBM for identification 
of primary site 
8.3 Exclusion criteria 
• 
Primary site identified by any means prior to being indicated for TBM 
• 
Patients undergoing targeted biopsies or resections 
• 
Patients known to have a history of previous H&N cancers 
• 
Patients known to have undergone previous radiation to the H&N region 

MOSES Protocol v4.2 
 
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IRAS: 256047 
CCR: CCR5065 
Page 11 
9 Study procedure and methodology 
9.1 Patient identification 
Patients will be identified from the MDT lists from participating centres which will be screened weekly 
by local leads. Those satisfying inclusion and exclusion criteria will be approached to take part. 
Additionally, for the patient interview qualitative component, local teams may mention the study to 
patients who have been previously treated with tongue base mucosectomy during their routine follow 
up appointments. The MOSES study team will not approach any of these patients directly. Adverts will 
also be places at peopleinresearch.org and at mosesstudy.co.uk for people to self-refer. 
9.2 Consent 
Once identified, eligible patients may be approached by the usual care team or research nurse either 
remotely or in person. No additional outpatient appointments or patient contacts should be required. 
Patients will be provided with copies of the Patient Information Sheets
Patient Information Sheets
Patient Information Sheets
Patient Information Sheets (PIS) and Informed Consent 
Informed Consent 
Informed Consent 
Informed Consent 
Forms
Forms
Forms
Forms (ICF). Appropriate time will be given to patients to read and digest the information. Written 
consent will be taken by an appropriately trained member of the clinical team or a research nurse.   
Re-consent 
Following the implementation of protocol v4.1, patients who had already consented using ICFs prior to 
v3.0 may be re-approached, by an appropriately trained member of the local team, to re-consent to 
the study to be able to participate in the extended follow-up and molecular analyses.  
Qualitative interviews 
For the Qualitative Interviews, consent may be completed remotely by the patient and the MOSES 
team. As with face-to-face consent, the Patient Information Sheet should be provided, and the patient 
given adequate opportunity to ask questions about participation in the study. An electronic copy of the 
consent form will be stored in the Trial Master File by the Sponsor.  
9.3 Functional outcomes and pain scores. 
Patient will be asked to complete 10 sets of questionnaires: at baseline (pre-operatively); and post-
operatively at 3 weeks, 6 weeks, 3 months, 6 months, 12 months, 24 months, 36 months, 48 months 
and 60 months. Patients will be asked to record their pain score at its worst, at its least and most of the 
time, on a Numeric Rating Scale. They will be asked to assess their swallow function by completing a M. 
D. Anderson Dysphagia Inventory (MDADI). Questionnaires may be completed in person, via post or 

MOSES Protocol v4.2 
 
 18 March 2022 
IRAS: 256047 
CCR: CCR5065 
Page 12 
remotely (including telephone, video-call or electronic form) and returned to the MOSES team on the 
contact email provided. 
9.4 Dataset and case report form (CRF) 
The following fields will be recorded on the CRF (please see the MOSES CRF document for full list):  
• 
Demographics 
• 
Medical history 
• 
Surgical history 
• 
Investigations 
• 
Peri-operative outcomes 
• 
Conventional histology result 
• 
Initial treatment plan 
• 
Pain and swallowing function scores 
• 
SSS histology result 
• 
Oncological status, including disease recurrence and primary emergence 
• 
Management of further disease 
• 
Participation in clinical trial(s) 
Data collected on the CRF can be used as source data.  
9.5 Pseudonymisation  
Each site will generate a unique study ID and use a ‘key’ to reference this to the NHS and hospital 
medical record number. This key will be stored locally at contributing trusts on an excel file on the hard 
drive of a secure NHS computer. The study key will be stored for the duration of the study and then 
destroyed in line with local processes for handling patient identifiable data. No patient identifiable data 
will leave the contributing trusts. 
A case report form (CRF) will be created for each patient to record the above dataset including the 
unique study ID. This information will be shared with the central MOSES team via nhs.net mail to a 
central MOSES computer held at the Royal Marsden Hospital in the H&N office.  
The central MOSES team will only receive and process pseudonymised data associated with the study 
ID. The central MOSES database will not record contributing sites by name so that individual cases are 
not linkable to their site of origin. The key to this information will be kept separately to the MOSES 
database.  
Study ID will be formed from a three letter hospital code followed by a three digit consecutive number, 
e.g. RMH001, RMH002, etc.  

MOSES Protocol v4.2 
 
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IRAS: 256047 
CCR: CCR5065 
Page 13 
9.6 Surgical technique 
All centres known to be performing TBM in the UK will be invited to take part. The surgery will take part 
at the contributing centre adhering to their usual practices. This will encompass techniques using laser 
resection, endoscopically assisted techniques and resections using robotic systems. There is currently 
no standardised method for performing TBM. An affiliated project will look to generate a standard 
operating protocol (SOP) for TBM for potential future studies. The technique used in each case will be 
recorded on the CRF. 
9.7 Handling of tissue specimens and histological processing  
All tissue will undergo conventional histological processing at the local site and will be used to influence 
patient management by the local team according to local practices. The following tissues will then be 
requested to be sent by the local teams to RMH for further analysis: 
• 
Oropharyngeal tissues from diagnostic surgeries attempting to identify the primary site (i.e., TBM 
specimens, and tonsils, if available) 
• 
Cervical nodal specimens, from the diagnostic neck biopsies (fine needle aspiration cytology and/or 
core biopsies) and/or therapeutic neck surgeries, if available 
• 
A buccal swab and/or blood sample (for germline DNA) 
Where SSS is indicated (TBM and tonsil specimens, if available) the MOSES team will then send these 
tissues onto the RVI. Appropriate tissue handling practices will be observed. RMH uses FreezerPro 
Laboratory Management Software to facilitate handling and tracking of tissue specimens.  
Anonymised histopathology reports will be requested from local centres. The macroscopic description 
will be used to orientate the submitted tissue blocks undergoing step serial sectioning. 
Step serial sectioning 
The paraffin blocks supplied from TBM and tonsil specimens will undergo step serial sectioning using 
the following method:  
• 
Steps every 0.5mm with five serial 4µm sections taken.  
• 
Each block will be processed in this way until the material is consumed.  
• 
Slides will be stained with haematoxylin and eosin stain (H&E) and examined for signs of SCC. 
• 
If an SCC is identified, then serial sections 2 and 4 will be submitted for HPV testing (p16 
immunohistochemistry and high-risk HPV DNA in situ hybridisation).  
• 
Serial sections 1 and 5 will be retained for repeat tests if required.  
• 
The pathologist will compose a report and complete the relevant sections of the CRF.   
• 
Unused material will be returned to the contributing centres if desired. Some material may be 
retained for further study, as detailed in the PIS and ICF. 

MOSES Protocol v4.2 
 
 18 March 2022 
IRAS: 256047 
CCR: CCR5065 
Page 14 
Exploratory molecular analysis 
Patients will be asked to provide buccal swabs and/or blood samples for germline DNA analysis. These 
samples may be provided at any time point following recruitment.  
Packaging and sending 
All MOSES blood and/or buccal swab samples should be collected, labelled, stored and shipped as 
detailed in the MOSES Sample Collection Manual
MOSES Sample Collection Manual
MOSES Sample Collection Manual
MOSES Sample Collection Manual.  
The buccal swabs and/or blood samples will likely be obtained during a face-to-face contact as part of 
the patient’s usual care pathway. In circumstances where samples cannot be obtained during a face-
to-face contact, the local site team may send a research pack
research pack
research pack
research pack (supplied by the sponsor) to the 
participant, via post, containing the blood and buccal swab collection materials for those agreeing to 
re-consent.  The pack will also contain the Cover Letter, PIS and ICF. The completed documents and 
sample collection materials may then be returned to the local site team using return labels, before 
being sent onto RMH as per the MOSES Sample Collection Manual
MOSES Sample Collection Manual
MOSES Sample Collection Manual
MOSES Sample Collection Manual. 
All samples must be labelled with the participant’s study identifier, date of birth and date of sample to 
enable cross-referencing. All samples should be sent by post to the following address:  
Dr Ben O’Leary 
2S8 
Chester Beatty Labs 
The Institute of Cancer Research  
237 Fulham Road, London SW3 6JB 
9.8 Qualitative methods and data outcomes 
Patients eligible for inclusion in the prospective cohort study will also be asked on the consent form if 
they would be happy to be contacted by a trained member of the MOSES team to be interviewed about 
the following topics:  
• 
Their views on the patient pathway to date. 
• 
Their views on TBM. 
• 
Their views on CUP in H&N and the psychological impact of not knowing the origin has 
been identified. 
• 
Their views on the potential diagnostic improvements brought by SSS 
• 
Their views on the possible escalation of treatment brought about by identification and 
incomplete removal of a primary 
• 
Their views on robotic surgery in general 
There is a separate patient information sheet and informed consent form for this qualitative 
component. Patients not consenting to be contacted regarding the above interviews will not be 
precluded from participation in the remainder of the study.  

MOSES Protocol v4.2 
 
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IRAS: 256047 
CCR: CCR5065 
Page 15 
After appropriate training in qualitative research methodology, a core committee will meet to agree a 
final methodology, form a provisional topics list and suggest interview questions. We will then engage 
with a PPI group to assess topic lists and questions and to hold practice interviews with appropriate 
feedback. Patients will be recruited for one-to-one interviews at various stages of their treatment.  
The interviews will be recorded, and a transcription of the conversation made. The transcription will be 
reviewed and coded using appropriate software. There will be interval thematic analysis and further 
recruitment/interviews until saturation (as per Francis method) before final thematic analysis [8]. No 
patient identifiable data will be recorded as per the methods above. Basic treatment information will 
be recorded alongside demographics to give context to the answers. 
Following the COVID-19 pandemic, it was clarified with the sponsor that remote consent and conduct 
of qualitative interviews would be acceptable for appropriately informed and consenting patients.  

MOSES Protocol v4.2 
 
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IRAS: 256047 
CCR: CCR5065 
Page 16 
10 Assessment timings 
10.1 Summary tables 
The following tables summarises the time points at which respective data fields will be gathered and 
returned: 
 
Procedure
Procedure
Procedure
Procedure 
Screen
Screen
Screen
Screen
ing
ing
ing
ing/ / / / 
Day 0
Day 0
Day 0
Day 0 
3 
wks
wks
wks
wks. 
6 
wks
wks
wks
wks. 
3 
mos
mos
mos
mos. 
6 
mos.
mos.
mos.
mos. 
12
12
12
12 
mos.
mos.
mos.
mos. 
 
24
24
24
24 
mos.
mos.
mos.
mos. 
 
36
36
36
36 
mos.
mos.
mos.
mos. 
 
48
48
48
48 
mos.
mos.
mos.
mos. 
 
60
60
60
60 
mos.
mos.
mos.
mos. 
Local 
team 
Eligibility
x
Informed 
Consent 
x 
 
 
 
 
 
 
 
 
 
Medical and 
surgical history 
x 
 
 
 
 
 
 
 
 
 
Investigation 
results 
x 
 
 
 
 
 
 
 
 
 
Conventional 
histology result 
 
x 
 
 
 
 
 
 
 
 
CRF Completion 
Page 
1-2 
Pages 
3, 4, 5 
 
 
 
Page 
6 
ICF v3.0 
and 
above 
 
Page 
7 
ICF v3.0 
and 
above 
 
Page 
8 
ICF v3.0 
and 
above 
 
Page 
9 
ICF v3.0 
and 
above 
 
Page 
10 
Patient/ 
Local 
team 
Pain  
questionnaire 
x 
x 
x 
x 
x 
x 
ICF v3.0 
and 
above 
ICF v3.0 
and 
above 
ICF v3.0 
and 
above 
ICF v3.0 
and 
above 
MDADI 
questionnaire 
x 
x 
x 
x 
x 
x 
ICF v3.0 
and 
above 
ICF v3.0 
and 
above 
ICF v3.0 
and 
above 
ICF v3.0 
and 
above 
 
Return of data
Return of data
Return of data
Return of data 
Screen
Screen
Screen
Screen
ing
ing
ing
ing/ / / / 
Day 0
Day 0
Day 0
Day 0 
3 
wks.
wks.
wks.
wks. 
6 
wks.
wks.
wks.
wks. 
3 
mos.
mos.
mos.
mos. 
6 
mos.
mos.
mos.
mos. 
12
12
12
12 
mos.
mos.
mos.
mos. 
 
24
24
24
24 
mos.
mos.
mos.
mos. 
 
36
36
36
36 
mos.
mos.
mos.
mos. 
 
48
48
48
48 
mos.
mos.
mos.
mos. 
 
60
60
60
60 
mos.
mos.
mos.
mos. 
Local team to  
return CRF to RMH 
x 
x 
 
 
 
x 
ICF v3.0 
and 
above 
ICF v3.0 
and 
above 
ICF v3.0 
and 
above 
ICF v3.0 
and 
above 
Local team to 
return questionnaires to 
RMH 
x 
x 
x 
x 
x 
x 
ICF v3.0 
and 
above 
ICF v3.0 
and 
above 
ICF v3.0 
and 
above 
ICF v3.0 
and 
above 
Local team obtain germline 
DNA samples (buccal swabs 
and/or blood samples) 
Any time point 

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in person or posted to 
patient 
Local team return tissues to 
RMH (TBM +/- tonsil 
specimens, cervical nodal 
specimens and buccal swab 
and/or blood samples) 
Any time point 
 
10.2 Pragmatic interpretation of timepoints 
The timepoints above are intended to collect data at the following points in the patients care: 
• 
Baseline 
Prior to TBM surgery 
• 
3 weeks 
Following TBM surgery 
• 
6 weeks 
Just prior to starting radiotherapy (if applicable) 
• 
3 months 
Just after completing radiotherapy (if applicable) 
• 
6 months 
- 
• 
12 months 
- 

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11 Data management 
The study will require a database to store pseudonymised data. Patient data will be collected on a paper 
case report form (CRF) at each site. The CRF will contain no patient identifiable data and will be 
pseudonymised with a study ID. The CRFs will be sent to the MOSES team at RMH. This will be entered 
onto an excel spreadsheet held on an NHS trust computer at the sponsoring organisation, the Royal 
Marsden Hospital NHS Foundation Trust. 
All patient identifiable data will remain at the local site subject to normal data governance practices. 
None will be sent to or handled by the project management team, except for those consenting to the 
qualitative study who agree to share their name and contact details on the main study ICF.  

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12 Statistics and data analysis 
12.1 Sample size 
No a prior sample size calculation was performed as initial funding limited recruitment to analysis of 60 
specimens to undergo SSS. Meta-analysis shows a pickup rate of 58% for this cohort. We anticipate a 
potential increase pick up rate of around 10%.  
• 
With 60 specimens, the 95% confidence interval boundaries around the pickup rate are +/- 
12.6% for 58% and +/-11.4% for 68%.  
In anticipation of further funding, our sample size is increased to 100 to give greater confidence in the 
effect size.  
• 
With 100 specimens, the 95% confidence interval boundaries around the pickup rate are +/- 
9.8% for 58% and +/-9.0% for 68%.  
12.2 Study endpoints 
For the Primary objective:  
• 
Identification of cancer in the tonsillectomy or TBM specimen on histology.  
For the Secondary objectives: 
• 
To compare the pick-up rate of primary cancers in TBM specimens between surgical methods 
(robotic vs laser vs endoscopic). 
o Identification of cancer in the tonsillectomy or TBM specimen on histology. 
o We anticipate no significant disparity in pick up rate between methods with the 
limited number of cases in this study.  
• 
To prospectively evaluate swallowing function and pain scores after TBM. 
o We anticipate no significant change in means from pain and MDADI scores between 0 
and 6 week questionnaires. Results at 3 weeks are anticipated to be different as still 
recovering from surgery. Results up to 60 months will evaluate effects of any 
subsequent treatments and future recovery. 
• 
To understand patient views and experiences of undergoing TBM for suspected HNSCCUP. 
o Qualitative thematic analysis therefore no quantitative end point.  
• 
To report time-to-event data for local, regional and distant disease recurrence, and mortality. 
o Primary emergence rate of around 3% per year. 
• 
To assess the molecular makeup of patients with suspected HNSCCUP undergoing TBM. 
o (Exploratory analysis) 

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12.3 Study duration 
Recruitment of patients will continue until 100 patients are recruited and undergo TBM. The study 
duration will be extended as necessary until this target is met across all centres. 
The study will remain open until the last patient to be recruited has completed their final 60 month 
follow-up.  Thereafter, end of trial definition will be dependent on resolution of all data queries and 
completion of database entries in preparation for final statistical analysis and subsequent publication.  
Once these stages have been reached and the study paperwork is ready for archiving, a ‘Declaration of 
End of Study Form’ will be sent to RMH R&D and to the Research Ethics Committee (Health Research 
Authority) notifying them that the study is now concluded.   A summary of the final research report will 
be provided to the Committee within 12 months of the conclusion of the study. This will report on 
whether the study achieved its objectives, summarise the main findings, and confirm arrangements for 
publication or dissemination of the research including any feedback to participants. 
Summary of project timings (correct at time of drafting v2.2) 
 
Date
Date
Date
Date 
Activity
Activity
Activity
Activity 
Dec 2018
First draft of protocol
Jan 2019
Protocol submission to sponsor (CCR)
Feb 2019
CCR review 
May 2019
Submission via IRAS
July 2019
REC/HRA approvals
Nov 2019
Opening of first sites
March 2020
COVID-19 disruption
October 2023
Completion of recruitment
October 2028
Completion of 60 month follow up for all patients
12.4 Analysis methods 
Descriptive analysis only is anticipated. The rate of CH and SSS pick up will be reported in the overall 
specimens and separately in the sub-group of surgical methods with 95% confidence intervals. The pain 
scores and swallow recovery with MDADI scores will be reported using mean/median and standard 
deviation or range as appropriate at each time point of 0, 3 weeks, 6 weeks, 3 months, 6 months and 
12 months, 24 months, 36 months, 48 months and 60 months. Similarly, score change between time 
points will be summarized in the same way. The primary and secondary analysis will be done when the 
complete sample size is recruited and last patient on the study completed all follow-ups. 
Molecular data analysis 
Detailed description of the molecular analysis methodology is beyond the scope of this protocol.  

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12.5 Safety Considerations 
There are no immediate safety implications anticipated due to the observational and non-
interventional nature of the study.  
There is potential for primary cancers to be identified in some tissue specimens where it had been 
missed at the local site when undergoing conventional histology. These updated results from the 
pseudonymised specimens will not be available in a timeframe that could influence patient treatment.  
12.6 Follow-Up 
The final patient questionnaires are completed at 60 months post-operatively. Outcome data is derived 
from the tissue specimens. As above, results from SSS of the tissue specimens will not be fed back to 
the individual MDT as it will have no potential to influence management which will already have been 
enacted.  
12.7 Quality Assurance 
The core MOSES team handling the pseudonymised data have all undergone GCP training with valid 
contemporary certification. 
12.8 Expected Outcomes of the Study 
TBM is a relatively new surgical procedure with little data relating to patients experience and recovery 
from this operation. The pain and MDADI questions will go some way to showing the acceptability of 
this procedure to patients. It is expected that by 6 weeks the pain and MDADI scores will have returned 
to near baseline. Most patients will go on to receive radiotherapy to their pharyngeal mucosa, which is 
known to worsen swallowing function. This data will go some way to clarifying that any subsequent 
difficulties may not be attributable to the TBM procedure.  
Any increased pick up rate resulting from SSS could lead to wider adoption of this process in the 
management of HNSCCUP. The size of any primary sites identified through SSS over conventional 
histology will also be recorded and could influence the size of histological levels employed for future 
TBM and tonsillectomy specimens in the future management of HNSCCUP.  
Data from the patient interviews and thematic analysis should help to guide patient goals for any 
further research in HNSCCUP. Of particular note will be the patients’ wishes regarding timing of the 
tonsillectomy and TBM procedures, which can occur separately, particularly if initial investigation is 
performed in a peripheral hospital that does not offer TBM. The potential changes in management from 
identification of primary sites using SSS, and potential for escalation of treatment through the addition 
of concomitant chemotherapy will also be novel.  

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Results from the exploratory molecular analysis are expected to give us greater understanding of the 
molecular make-up of suspected HNSCCUP. Including, but not limited to, how cancers where the 
primary is identified differ from those primaries that remain occult, and how the cervical disease differs 
from primary site tissues in the oropharynx. 
Results from this prospective observational study will form the foundation of a potential phase III trial 
investigating the roles of TBM and SSS in management of suspected HNSCCUP. The precise research 
question is yet to be established. 
12.9 Dissemination of Results and Publication Policy 
Findings from the study will be submitted for publication in relevant H&N peer reviewed journals. JH 
will be lead author and VP will be last author on papers, with MR and KH also included as senior authors. 
The Principal Investigators at each site will be included as authors, as per journal policy and following 
review and approval of the final manuscripts.  
BOL will lead on analysis, dissemination and publication of work related to the exploratory molecular 
analysis.  
Following completion of the study, we plan to run a consensus day for management of HNC of unknown 
primary. The published and unpublished data from this study is intended to contribute.  

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13 Problems Anticipated 
13.1 Slow recruitment of TBM centres 
Early contact with the TBM centres across the UK should improve timely recruitment. 
13.2 Slow recruitment of TBM patients 
It is very unlikely that any eligible patients will be missed by the MDTs and clinicians involved in 
recruitment. It is also felt to be unlikely that patients will not consent to being involved in the study as, 
by design, there has intended to be minimal burden from the questionnaires.  

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14 Project Management 
Name
Name
Name
Name 
Vinidh Paleri
Role(s)
Role(s)
Role(s)
Role(s) 
Chief investigator
Responsibilities
Responsibilities
Responsibilities
Responsibilities 
Oversight of project design, conduct and reporting. 
Liaison with Research Ethics Committee (REC), and other review bodies, during 
the application process, and where necessary during, the conduct of the 
research. Ensure adherence to protocol.  
Analysis and write up of MOSES findings 
 
Name
Name
Name
Name 
Max Robinson
Role(s)
Role(s)
Role(s)
Role(s) 
Co-investigator
Chief pathologist 
Responsibilities
Responsibilities
Responsibilities
Responsibilities 
Coordination of processing of pathology specimens once received at Newcastle 
laboratories and reviewing of slides for diagnosis of primary outcome of MOSES 
trial.  
Analysis and write up of MOSES findings 
 
Name
Name
Name
Name 
John Hardman
Role(s)
Role(s)
Role(s)
Role(s) 
Co-investigator
Clinical research fellow 
Responsibilities
Responsibilities
Responsibilities
Responsibilities 
Recruitment of contributing centres. 
Coordination of centralising pathology specimens to Newcastle laboratories 
Coordination of data governance and control of the MOSES database.  
Tabulation of data from questionnaires. 
Analysis and write up of MOSES findings and MOSES Qualitative findings 
 
Name
Name
Name
Name 
Kevin Harrington
Role(s)
Role(s)
Role(s)
Role(s) 
Co-investigator
Professor of oncology 
Responsibilities
Responsibilities
Responsibilities
Responsibilities 
Academic supervision of JH
Analysis and write up of MOSES findings 
 
Name
Name
Name
Name 
Ben O’Leary
Role(s)
Role(s)
Role(s)
Role(s) 
Co-investigator
Oncologist 
Responsibilities
Responsibilities
Responsibilities
Responsibilities 
Exploratory molecular analysis
 
Name
Name
Name
Name 
Grainne Brady
Role(s)
Role(s)
Role(s)
Role(s) 
Co-investigator
Speech and Language Therapist 
Responsibilities
Responsibilities
Responsibilities
Responsibilities 
Qualitative researcher
Analysis and write up of MOSES Qualitative findings 
 
Name
Name
Name
Name 
Mary Wells
Role(s)
Role(s)
Role(s)
Role(s) 
Co-investigator
Professor of Nursing 
Responsibilities
Responsibilities
Responsibilities
Responsibilities 
Qualitative researcher
Analysis and write up of MOSES Qualitative findings 

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15 Ethical considerations 
The protocol will be submitted for ethical review to the Human Research Authority’s ‘Integrated 
Research Application System’ (IRAS). It is believed the application will be suitable for a ‘proportionate 
review’ which allows fast tracking of the process. 
Having undergone SSS, the tissue specimens may have new or additional carcinomas identified. This 
information will not be available to the treating MDT in a timeframe that could influence patient care. 
Their treatment plans will have been enacted. The results of the pathological processing will not be fed 
back to the contributing centres but will only be held in a pseudonymised central MOSES database.  
Patients will be asked to complete pain score questionnaires and swallowing function questionnaires. 
Many centres collect swallow function scores for head and neck cancer patients routinely. These 
questionnaires will be an additional burden to these patients. However, it is also acknowledged that by 
asking for these data it may prompt closer attention and better care for these patients. 
Patients approached to take part in one-to-one interviews have potential to discuss their perceptions 
regarding their cancer and cancer management. This could be potentially distressing for some patients. 
They will be provided with appropriate contact information for Clinical Nurse Specialists throughout the 
process. They are also eligible to withdraw from the process at any stage without any impact on their 
care. It is likely that the majority of the patients will have completed their treatment and be in 
surveillance by the time they are approached to be involved in the interviews.  

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16 Informed consent process 
16.1 Informed Consent Forms 
Please see appendix for PISs and ICFs. 
Consent for the qualitative interviews is distinct from consent to the main study.  
See ‘consent’ in Section ‘Study procedures and methodology’ for further information on the consent 
process.  

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17 Budget 
17.1 Approved funding 
This study has been funded by a grant from Oracle Cancer Trust. The following is a summary of the 
costings for the grant application that were revised and approved on 3rd December 2018: 
 
Item
Item
Item
Item 
 Total 
Total 
Total 
Total  
 Comment 
Comment 
Comment 
Comment  
TOTAL COST 
TOTAL COST 
TOTAL COST 
TOTAL COST 
OF PROJECT 
OF PROJECT 
OF PROJECT 
OF PROJECT  
Pathological processing 
 £           30,937.50 
(£475.96/case)  
Clinical research fellow 
 £           50,538.09 
Total for 2 yrs  
 
MD registration fees (ICR) 
 £             9,220.00 
(£4,610 /yr)  
Qualitative Research Methods 
Course 
 £             1,525.00 
https://bit.ly/2DXIbxY 
 
Supervising PI (Prof Vin Paleri) 
 £           11,567.00 
(2hrs/wk)  
 
Dr Max Robinson (pathology lead) 
 £             9,203.80 
(2hrs/wk)  
 
Consensus meeting 
 £             5,000.00 
ORACLE 
ORACLE 
ORACLE 
ORACLE 
GRANT 
GRANT 
GRANT 
GRANT 
REQUESTED 
REQUESTED 
REQUESTED 
REQUESTED  
TOTAL 
TOTAL 
TOTAL 
TOTAL  
 £         117,991.39 
£         117,991.39 
£         117,991.39 
£         117,991.39   
Per Annum 
 £           58,995.70 
over 2 yrs  
This study received a further grant from the Biomedical Research Centre TPT Pump Priming fund. This 
award of £20,000 will cover Human Tissue Bank costs at RMH and the receipt and transfer of tissue 
from the contributing units to the laboratory at the RVI in Newcastle. It will also cover reimbursement 
of patient travel costs, room hire, basic catering/tea/coffee, interview transcription and a licence for 
the NVIVO coding analysis software for the qualitative interviews. 
Statistics and database costs were expected to be around £10,000. However, these costs are no longer 
applicable, following the award of the TPT Pump Priming grant above. 
17.2 Outstanding funding 
An application has been made to the Get A-Head charity for continued funding to cover extended 
recruitment, follow-up and to obtain tissue samples for the exploratory molecular analysis.  
17.3 Other support for the Project 
We are grateful for the support from Oracle Cancer Trust, the Royal Marsden Hospital, the Institute for 
Cancer Research and Newcastle upon Tyne Hospitals NHS Foundation Trust.  
The salary for the Clinical Research Fellow has also received contributions from the Royal College of 
Surgeons of England and ENT UK.  

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18 Collaboration with other scientists or research institutions 
18.1 Curriculum Vitae of investigators 
The CV of the Principal investigator will be provided.  
18.2 Other research activities of the investigators 
Current research projects that the principal investigator is involved in are listed in the appended CVs, 
including the source of funding of these projects, the duration of those projects and the percentage of 
time spent on each. 

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19 Financing and Insurance 
Financing has been outlined in the ‘Budget’ section above.  
Insurance is as per Sponsors arrangements.  
 

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20 References  
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unknown primary with metastatic neck disease: United Kingdom National Multidisciplinary 
Guidelines. The Journal of Laryngology & Otology. 2016;130:S170–5.  
2. Galloway TJ, Ridge JA. Management of Squamous Cancer Metastatic to Cervical Nodes With an 
Unknown Primary Site. J Clin Oncol. 2015;33:3328–37.  
3. Cancer of the upper aerodigestive tract: assessment and management in people aged 16 and over 
| Guidance and guidelines | NICE [Internet]. [cited 2018 Dec 3]. Available from: 
https://www.nice.org.uk/guidance/ng36/chapter/Recommendations#investigation 
4. Winter SC, Ofo E, Meikle D, Silva P, Fraser L, O’Hara J, et al. Trans-oral robotic assisted tongue 
base mucosectomy for investigation of cancer of unknown primary in the head and neck region. The 
UK experience. Clin Otolaryngol. 2017;42:1247–51.  
5. Wallis S, O’Toole L, Karsai L, Jose J. Transoral endoscopic base of tongue mucosectomy for 
investigation of unknown primary cancers of head and neck. Clin Otolaryngol. 2018;  
6. Black CC, Ogomo C. Does pTis exist in HPV-driven tonsillar carcinomas? An ultrastructural review 
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7. Genden EM. The role for surgical management of HPV-related oropharyngeal carcinoma. Head 
Neck Pathol. 2012;6 Suppl 1:S98-103.  
8. Francis JJ, Johnston M, Robertson C, Glidewell L, Entwistle V, Eccles MP, et al. What is an adequate 
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