Trial Information

National Anaplastic Thyroid Cancer Tissue Bank and Database (NATT). A UK Research Tissue Bank

Study design and methodology

ATC patients will be identified by thyroid cancer specialists (including endocrine surgeons,
head and neck cancer surgeons, clinical oncologists, endocrinologists, pathologists,
radiologists, clinical nurse specialists) working in thyroid cancer multidisciplinary teams
(MDTs) across the UK Cancer Networks.

Patients will be approached by a member of the MDT and provided with a patient information
leaflet on the National Anaplastic Thyroid Cancer Tissue Bank and Database project.
Following discussion and adequate time to consider the project, the patient will be invited
to participate and to provide their written consent.

Consent will be sought for thyroid tissue collection, blood sample collection as well as
collection of anonymised clinical data.

It is expected that the majority of patients will be willing to participate as their own
care will be unchanged but they have the potential to help future patients in the same
difficult situation.

As entry into the study will not affect the patient's own care there is no time limit after
diagnosis in which participation can be undertaken.

As the majority of the patients will not have anaplastic thyroid cancer that is amenable to
total thyroidectomy the tissue specimen collection will usually entail diagnostic core
biopsies or fine needle aspirates from the thyroid gland. The tissue specimens will
initially be used for histological diagnosis at the local hospital and any spare tissue will
then subsequently be sent to the Wales Cancer Bank (WCB) 3. In the minority of patients who
undergo some form of thyroid resection, tissue blocks and possibly slides will be sent for
storage at WCB once the initial diagnostic work is complete.

An optional EDTA blood samples will also be collected and sent to WCB. Patients will ideally
provide both tissue and blood samples but can opt to submit one or other specimen type if
they prefer.

A multidisciplinary steering committee will be established to oversee the running of the
project and to review subsequent independently submitted research proposals.

A baseline Case Report Form (CRF) will be completed and forwarded to WCB. Where consent has
been given for the collection of clinical data this will be entered either by the patient's
own thyroid consultant or by Dr Moss into the secure and confidential Thyroid Cancer
Forum-UK4 database.

As ATC comprises a heterogeneous group of histological appearances that often prove
difficult to accurately diagnose, a central pathological review process will be implemented
to ensure uniform pathological reporting. An opportunity for molecular profiling of
individual tumours will also be considered at this stage.

Outcome data will be requested at 6, 12, 18months and annually thereafter. However as the
prognosis is generally poor with current treatment options, outcome data collection is
unlikely to extend beyond 6 months in the majority of cases.

ATC disease trajectory, response to treatment and outcomes (Progression Free Survival and
Overall Survival) will be correlated with histological appearance and molecular profile.

Patient identifiable data will only be accessible at the referring centre by the clinical
team caring for the patient but not at the National ATC Tissue Bank. Each patient will be
allocated a unique identification number by WCB and all stored data and specimens will use
this for reference only.

It is unknown with the currently available UK data on thyroid cancer incidence precisely how
many cases of anaplastic thyroid arise annually. It is estimated that 70-90 new cases are
diagnosed per year. The research project is expected to run for between 5 and 10 years in
the first instance to allow a significant number of patients to be included in the project.
Funding has been secured from Thyroid Cancer Support Group- Wales5.

Eligibility Criteria

- All patients with anaplastic thyroid cancer who are able to provide informed consent.

- Patients with foci of anaplastic thyroid cancer within a more differentiated thyroid
cancer who are able to provide informed consent.

Exclusion Criteria

- Patients with non anaplastic thyroid cancer including medullary thyroid cancer,
papillary thyroid cancer, follicular thyroid cancer, thyroid lymphoma

- Patients unable to provide informed consent

Identification of Patients

Patients may be discussed and identified at a thyroid cancer or head and neck cancer
multidisciplinary team meeting. Identification may arise from pathologist, radiologist,
clinicians or clinical nurse specialists.

Due to the expected short survival of this patient group it would be prospective
identification of patients and not a retrospective review of previous cases.

Patients will be approached by a member of the team either on an inpatient ward or in the
out patient clinic only once the diagnosis is confirmed, the patient is aware of their
diagnosis and have had sufficient time to come to terms with the diagnosis.

Patient Recruitment and Registration

Patients with a confirmed diagnosis of anaplastic thyroid cancer and who are aware of their
diagnosis and able to provide informed consent would be considered.

Appropriate patients would receive a verbal explanation of the study in the first instance
followed by a written information leaflet.

The patient would then be given as much time as they need to decide if they wish to
participate. For those wishing to proceed, a member of the thyroid cancer multidisciplinary
team will go through the consent process and consent form with them. They will answer any
questions and highlight the optional parts of the study. The patient would be given a copy
of the consent form including contact details for the local thyroid cancer team lead and the
Chief Investigator.

No patients from vulnerable groups would be approached. Information on the tissue bank and
database project will be posted on the Thyroid Cancer Forum-UK (TCF-UK) and Thyroid Cancer
Support Group- Wales websites as well as announced at national and international thyroid
cancer meetings and in the medical press. Other UK thyroid cancer patient support groups
will be kept informed of the project as they will be in contact with anaplastic thyroid
cancer patients and their families. The project will also be registered and displayed on the
www.clinicaltrials.gov website.

Sample Collection and Storage

It is expected that the vast majority of patients will already have had biopsies or Fine
Needle Aspirates (FNA) taken from their thyroid gland in order to make the diagnosis in
which case it is these samples that will be sent to the tissue bank. Occasionally diagnostic
biopsies will have been retrieved from anatomical sites other than the thyroid gland
including, but not confined to, cervical lymph nodes and distant metastases.

Only tissue samples that are no longer required by the local pathology department will be
sent to the tissue bank. Due to the usual short prognosis for patients with this disease it
is not expected that the local pathology department will need to request the samples back in
order to undertake any further investigations at a later date in the patient's cancer
journey. However if this situation does arise then any unused samples will be returned as
requested.

The patient will be asked if they wish to donate an optional EDTA blood sample as part of
the research project and this sample will be taken when possible at the same time as any
routine clinically indicated blood samples to reduce the number of venepuncture procedures
required.

Data Collection and Storage

The patients will be asked if they wish for a summary of their clinical history including
details on their mode of presentation, any treatment interventions and complications (such
as requiring a tracheostomy or enteral feeding tube) to be included in the study. Thyroid
Cancer Forum-UK already has an established national anaplastic thyroid cancer database. This
is hosted on a secure website server and is registered with the Information Commissioner's
Office. The data on this is only accessible by Dr Laura Moss, as the project Chief
Investigator and TCF-UK data controller, and by the individual patient's consultant. This
system is already up and running for anaplastic thyroid cancer patients (and medullary
thyroid cancer patients) and no concerns have been raised from either the patient or
clinician perspective.

Quality Assurance

The patient's local thyroid cancer team will be responsible for liaising with the NATT
project/Wales Cancer Bank to attribute a unique identifier number to each study participant.

The patients' initials and unique identifier number will be used to identify subjects.

The Wales Cancer Bank (WCB) processes confidential and valuable data. The WCB Security
Policy aims to protect data against loss or destruction, and unauthorised access or
modification. It also ensures data integrity will be maintained.

The clinical data on the Thyroid Cancer Forum-UK database is stored on a secure website
server. The national data is only accessible by Dr Laura Moss (NATT Chief Investigator and
TCF-UK data controller). The patient's local team can only access data on their own patients
and not patients registered elsewhere in the UK. Data fields collected include patient
initials,

NATT unique identifier number, gender and date of birth. This information is required in
order to nationally assess age and gender distribution and to correlate with treatment
received and outcomes.

Ethical considerations

Research into anaplastic thyroid cancer has been thwarted by a combination of its rarity and
poor prognosis. A rare disease is often quoted as having an incidence of <2 cases per
100,000 and anaplastic thyroid cancer has an incidence of only 0.17 per 100,000 in Europe.
The rarity means it is very difficult to carry out prospective research without
collaboration amongst thyroid cancer teams. This project is designed to involve thyroid
cancer multidisciplinary teams across the UK and will seek to approach as many patients with
anaplastic thyroid cancer as possible.

The project has been discussed from an early stage with the National Cancer Research
Institute Thyroid Cancer subgroup and has its support.

Patient involvement in the project development was sought at an early stage from the two UK
thyroid cancer specific patient organisations, Butterfly Thyroid Cancer Trust and Thyroid
Cancer Support Group-Wales. The latter charity has subsequently committed themselves to
funding the entire project.

It is anticipated that the recruitment rate will be high as the patient will not need to
undergo any additional invasive procedure other than a blood test which is optional.
Patients will be aware that this is a rare disease with currently no effective therapy and
short prognosis so it is anticipated that there will be altruistic donations for the benefit
of future patients who face the same diagnosis. Patients will be approached by members of
their local thyroid cancer multidisciplinary team who are experienced in the management of
this disease and who have appropriate experience in consent procedures.

The database aspect of the project is not a new concept. Thyroid Cancer Forum-UK, has been
collecting the same data fields in the same manner for several years for patients across the
UK. The database project is registered with the Information Commissioner's Office.

Data will be collected in accordance with the Caldicott Principles and patient identifiable
data will be very limited.

Patients participating in the project face no physical risk as a result of their
participation in the project. Due to the anticipated timescale for collection of tissue and
data it is expected to take a minimum of several years before any meaningful outcomes will
be achieved. The poor prognosis of the disease means that the project participants are
unlikely to be alive when the subsequent research projects come to fruition and will not
therefore benefit directly from participation in the study.

The patient information leaflet explains the project objectives both in terms of what is
being asked of the individual patient in terms of donation of tissue, blood and data and
also stipulates that the samples will be stored pending submission of future research
proposals from respected researchers which will have the necessary ethical approvals and
will be scrutinised by the National Anaplastic Thyroid Cancer Tissue Bank and Database
(NATT) steering committee. Patients will be able to withdraw their consent at any stage,
without needing to provide a reason and will be made aware that any unused samples will
either be returned to their local hospital or disposed of in accordance with the Human
Tissue Authority code of practice and their data will be removed from the database. The
issue of consent withdrawal is not expected to be a significant problem.

Human tissue disposal It is recognised that all donations to the NATT project are altruistic
and patients are free to withdraw consent without reason at any time.

Patients are advised, at the time of consent, that some of their samples may already have
been used by the time they wish to withdraw.

It is acknowledged that the disposal of human tissue is a sensitive area and the project
will comply with the Human Tissue Authority code of practice, 'The removal, storage and
disposal of human organs and tissue'

Ethics Approval The project will be conducted in accordance with the World Medical
Association, Declaration of Helsinki (2008 version) and in accordance with the terms and
conditions of the ethical approval given to the trial.

Study management

Velindre NHS Trust Research and Development Department will be responsible for organising
Material Transfer Agreements between Velindre NHS Trust and each Tissue Collection Centre.
Individual investigators will liaise with their local R&D departments. They are then
responsible for recruiting patients, adhering to the most recent version of the protocol and
collection of data on the case report forms (CRFs).

The project will be overseen by a multidisciplinary steering committee comprising clinical
oncologists, Wales Cancer Bank manager, Velindre NHS Trust R&D management, thyroid cancer
scientists and pathologists. The committee will review the tissue sample collection in terms
of central pathology review to ensure consistency, rate of national recruitment, number of
centres participating and any potential limitations to patient recruitment into the project.

Publication

Any publications or presentations arising directly as a result of this project will
acknowledge all contributing investigators.

Summary

The aim of the project is to facilitate research opportunities into this difficult disease
which historically has been difficult to research due to the combination of its rarity and
overall poor prognosis. By utilising a national tissue and data resource model a significant
number of patients and samples can be studied in a realistic research timeframe. The project
has the potential to help with our understanding of the disease aetiology and to open new
avenues for treatment interventions.

As a result of the patient participating in this project they will be agreeing to any
surplus anaplastic thyroid cancer tissue plus a blood sample being sent to the Wales Cancer
Bank for storage until a suitable research project is approved by the National Anaplastic
Thyroid Cancer Tissue Bank and Database (NATT) Project Steering Committee. Participants also
have the option of having their clinical information collected in a pre-existing national
database. Participants will not be approached regarding any further tissue or blood samples.