Title: The efficacy and cost effectiveness of Real Time Ultrasound Elastography in the investigation of thyroid nodules and the diagnosis of thyroid cancer
Funder: Department of Health and Social Care

Abstract: DEFINITIONS: Please see Abstract below and diagram for definitions of different categories of the FNAC classification. DESIGN Pragmatic multicentre randomised trial with 1:1 randomisation, using the following minimisation variables: 1. Radiologist - as ultrasound is operator dependent. 2. Solitary nodule versus multi-nodular goitre - as multiple nodules can affect the utility and accuracy of RTE. 3. Size of nodule (<4cm vs. >4cm) - as size can affect accuracy of FNAC. 4. Completely cystic vs. solid or mixed solid and cystic nodules - as RTE cannot be used in a completely cystic lesion. INTERVENTION Real-time ultrasound elastography (RTE)–guided Fine Needle Aspiration cytology (FNAC). RTE is a technology that can be used at the same time as the routine ultrasound examination. RTE may help differentiate benign from malignant nodules based on the compression characteristics of the two (as benign nodules are less firm than malignant ones). This may then help reduce sampling errors and decrease the false negative rate of the first FNA, by guiding the radiologist to the nodule that is most likely to be malignant. RTE may also help guide the radiologist to the parts of large heterogeneous nodules that are most likely to contain malignant cells. This may also improve the nodule diagnostic rate (i.e. reduce the non-diagnostic rate). CONTROL Conventional grey scale and colour Doppler ultrasound-guided FNAC for all the FNACs required to obtain a definitive diagnosis for patients in the control arm. SETTING Secondary care radiology departments with radiologists who have undergone training and accreditation for RTE. Training and Accreditation: RTE is not yet commonly used in the UK, and so radiologists do not have experience in the technique. We have developed a training and accreditation module to address this. This will run concurrently in the first year with the set-up phase of the trial so that it does not delay the start of recruitment. It will include a workshop, a clinical observership, online tests and then a 'hot case' practical test, as well as second reading of the first 10 cases per radiologist. TARGET POPULATION Patients 18 years old or over with a thyroid nodule or nodules, detected on palpation by the clinician (clinically palpable) or identified incidentally by imaging performed for non-thyroid pathology e.g. cervical spondylosis. OUTCOME MEASURES Primary 1. The proportion of patients who have a non-diagnostic (Thy1) cytology result following the first FNAC. Secondary 1. Number of FNACs required to obtain a definitive diagnosis; 2. Time from first FNAC to obtaining a definitive diagnosis; 3. The proportion of patients with benign histology results following thyroidectomy; 4. Proportion of patients who have thyroidectomy; 5. Accuracy of a cytology result for first FNAC and repeated FNAC in relation to overall definitive diagnosis; 6. Accuracy of an imaging assessment on ultrasound (with or without RTE) alone diagnostic protocol in relation to overall definitive diagnosis; 7. Patient reported outcome measures of depression and anxiety, pain, and quality of life: the Hospital Anxiety and Depression rating Scale (HADS), Visual Analogue Pain Score (VAPS) and EQ-5D quality of life score; 8. Radiologist report of whether RTE had contributed to the radiologist's decisions, how easy they found using RTE, and whether they found it helpful above using US-alone in predicting malignancy; 9. Complication rate from any thyroidectomy at 30-days and 6-months post-surgery - to include haematoma rate and temporary hypocalcaemia rate rate at 30 days and vocal cord palsy and permanent hypocalcaemia at 6 months post-operative; 10. Resource usage for consultation time and diagnopstic testing procedures and subsequent management including consultations and surgical treatments. ASSESSMENT & FOLLOW-UP For both intervention and control arms, diagnosis and management will proceed as per the British Thyroid Association Guidelines for management of thyroid nodules. FNACs will be repeated until a diagnosis is obtained – either two benign (Thy2) FNAC results (patient can then be discharged), or one Thy2 FNAC with a benign ultrasound, or a Thy3/4/5 result necessitating surgery, or a decision is made to operate on a patient with at least 3 repeated Thy1 results (see diagram). QUALITY ASSURANCE Radiology The first 5 US elastography scans by each radiologist will be reviewed by the Trial Radiology Panel. Thereafter, a random sample of all scans will be reviewed by the Trial Radiology Panel. Cytology and histology All Thy 3,4 & 5 FNACs and a random sample of 5% of all Thy 1 & Thy 2 FNACs and all thyroidectomy histological samples will be reviewed by one of the experienced thyroid cyto/histopathologists of the Trial’s Reference Pathology laboratory. Any cases showing discordance between local and reference results will be reviewed by the full panel. Discordances will be fed back to the relevant pathologists. SAMPLE SIZE We will recruit a sample of 968 patients which will give over 90% power to detect a difference in the rate of non-diagnostic (Thy1) FNAC results at a 5% significance legel, allowing for 15% loss to follow-up. RECRUITMENT: 15 centres will recruit on average for 53 months, at a rate of 2.5 per month, or 30 patients per year, representing 25-30% of throughput of the interested centres. STATISTICAL ANALYSIS Analysis will be according to intention to test and treat principles at the patient level. TIMELINES 0- 18: set up of sites, and training and accreditation of radiologists. 6- 54: recruitment. 54-60: completion of follow-up. 60-72: trial closure, analysis and write-up. SUPPORTED BY: the British Thyroid Foundation (largest UK patient support group) and the European Society of Head and Neck Imaging.

Lay abstract: Thyroid lumps (nodules) are very common. About 1 in 20 people will feel a thyroid lump at some time in their life. About half of the population will have lumps in their thyroid if examined by ultrasound scan, but may not know they have them. About 1 in 20 of thyroid lumps are cancerous. Currently, the recommended way of examining and getting a diagnosis on thyroid nodules is by doing an ultrasound and using it to guide a needle (like the one used for taking blood) into the thyroid lump to get some cells from the lump. This process is called ultrasound-guided fine needle aspiration (US-FNAC for short). Doctors then examine the cells by microscope and can make a diagnosis of whether the lump is benign, malignant (cancerous), or that not enough cells could be obtained to make a diagnosis (called a non-diagnostic sample). The British Thyroid Association has classified the results of FNAC into 5 categories and recommended further management accordingly: CATEGORY THY 1 - NOT DIAGNOSTIC. One of the problems of FNAC is that about 20% of these procedures do not give a diagnosis (not enough cells obtained). This means that the FNAC needs to be repeated, which causes patients pain, and distress due to delayed diagnosis. In addition, if no diagnosis can be obtained after 3 biopsies, doctors recommend that the patient have an operation to remove that side of the thyroid to obtain a diagnosis. CATEGORY THY2 - BENIGN (not cancer). 70% of patients with nodules will have this result, which reassures them. However, ultrasound FNAC is not totally accurate - and it is wrong in 5% of times. Therefore, the Guidelines recommend that patients who have a Thy2 (benign-not cancerous) result need to have a second ultrasound FNAC to ensure that the result is very accurate (wrong in less than 1% of cases), before they can be discharged from the care of the doctor. CATEGORY THY 3 - FOLLICULAR INDETERMINATE. This result occurs in 5% of cases and means that special cells have been obtained which can be cancerous or not, but the FNAC will NOT be able to tell us which it is - so an operation is necessary to remove the half of the thyroid that has the nodule to get a definitive diagnosis. The nodule will turn out to be cancerous in about 20% of these cases, meaning that 80% will have a benign lump which did not need to be removed. It would be beneficial to find a way of improving this so that less thyroid operations are done for benign (non-cancerous) lumps. CATEGORY THY 4 - SUSPICIOUS OF CANCER. This result occurs in 3-4 % of cases. It means that the FNAC shows that this is highly likely to be cancer, and so an operation is performed to remove the thyroid gland. The nodule turns out to be cancerous in about 80% of these cases. CATEGORY THY 5 - DIAGNOSTIC OF CANCER. This result occurs in 1-2 % of cases. It means that the FNAC is almost certainly cancer, and so an operation is performed to remove the thyroid gland. The FNAC result in this case turns out to be correct in 98-99% of the time. A new technology, called real time ultrasound elastography (RTE), is now available that can be used in conjunction with the ultrasound-FNAC. It looks at the firmness of the thyroid lump and indicates whether it is likely to be cancer (hard lump) or benign (soft lump). This technology has been shown in small studies to have a high accuracy. So it may be possible that the use of elastography in addition to the ultrasound-FNAC may make the FNAC more accurate. Potentially therefore, this may mean that only one FNAC is required, rather than having to repeat it twice as currently happens. This would decrease the number of FNACs required to obtain a diagnosis. In addition, potentially elastography may also decrease the number of the FNACs that are not diagnostic. This would again decrease the need for repeating FNACs. In our proposed study, we will allocate patients who are to have ultrasound-FNAC of the thyroid randomly (by chance) to having: 1.an ultrasound guided-FNAC (US-FNAC), which is the current standard or 2. real time elastography and ultrasound guided-FNAC (RTE-FNAC, the new technology) Since elastography is a new technique, we will have a training and certification programme to ensure that radiologists are trained and have the experience to do elastography accurately. Outcomes: We will compare how well the two techniques identify cancerous nodules by comparing number of patients who have non-diagnostic results after the first FNAC performed. We will also compare the number of FNACs done by elastography that show a result (diagnostic biopsies) compared to those done by ultrasound alone. We will also compare the cost-effectiveness of the two techniques. We will also ask radiologists whether they felt elastography helped them. Sample size; we will need 968 patients to demonstrate if the number of patients who have a non-diagnostic (Thy1) first FNAC result will drop from 10% to 4%. Support for the study Both the the British Thyroid Foundation (the largest UK patient support group) and the European Society of Head and Neck Imaging (a large professional body for radiologists) strongly support the study (letters attached).

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS