Hemithyroidectomy or Total-Thyroidectomy in 'Low-risk' Thyroid Cancers

Study Overview
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Brief Summary
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This is a multi-centre, randomised, non-inferiority, phase III study in patients with low risk differentiated thyroid cancer. Patients will be identified via oncology multidisciplinary team meetings. There will be two sources of patients in the trial, with the same histological diagnoses and prognosis (i.e. recurrence risk): Group 1: Patients who have already had a HT for thyroid problems and are then subsequently diagnosed with low risk DTC will be randomised 1:1 to undergo surveillance only OR a second operation to remove the rest of their thyroid gland (two-stage total thyroidectomy). Group 2: Patients diagnosed with low risk DTC using cytology (Thy5) but no surgery performed will be randomised 1:1 to have either a hemi-thyroidectomy OR a single-stage total thyroidectomy. The overall aim of the trial is to determine whether hemithyroidectomy is an acceptable and cost-effective surgical procedure compared to total thyroidectomy in low risk thyroid cancer. Overall, 456 patients will be recruited to the trial. Patients will be initially be followed up post-surgery then 12 monthly for 6 years.

Official Title
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Hemithyroidectomy or Total-Thyroidectomy in 'Low-risk' Thyroid Cancers

Conditions
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Differentiated Thyroid Cancer

Intervention / Treatment
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* Procedure: Total Thyroidectomy
* Procedure: Hemithyroidectomy


Participation Criteria
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Eligibility Criteria
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Group 1 (HT already performed prior to diagnosis) Inclusion criteria • Aged 16 or over Papillary thyroid cancer: pT1b-2 (≤4cm) irrespective of molecular genetic markers R0 resection (clinically excised but microscopic R1 resected tumours at discretion of the local MDT) cN0 or pN0, pNX & pN1a (≤5 foci, no extranodal spread) Confined to thyroid or minimal extrathyroidal extension No higher risk histological variants on morphology (small foci allowed at the discretion of the local MDT) No angioinvasion NB. PTC is still eligible where microscopic invasion of endothelial lined small capillary vascular spaces and lymphatic channels are present. It becomes ineligible in the rare instances when there is definite invasion of a larger vascular structure such as a vein with smooth muscle in its wall. Encapsulated FVPTC with capsular invasion only Micro-PTC (≤1cm) multifocal unifocal with pN1a (≤5 foci; no extranodal spread) Follicular thyroid cancer (FTC), including oncocytic or Hürthle cell carcinoma: pT1b-2 (≤4cm) irrespective of molecular genetic markers - Minimally invasive, with capsular invasion +/- minimal (≤4 foci) vascular invasion (the latter is now called encapsulated angioinvasive and is at the discretion of the MDT) Confined to thyroid or minimal extrathyroidal extension Exclusion criteria >4cm unifocal pT1a (≤1cm) PTC or FTC (unless pN1a as above) NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) Anaplastic, poorly differentiated or medullary thyroid carcinoma R2 gross extrathyroidal extension pT4 or macroscopic tumour invasion of loco-regional tissues or structures pN1a with >5 foci or extranodal spread pN1b M1 Aggressive PTC with any of the following features: Widely invasive Poorly differentiated Anaplastic predominance of Tall cell, Columnar cell, Hobnail, Diffuse sclerosing and other higher risk variants FTC, including oncocytic or Hürthle cell cancer with any of the following features: Minimally invasive with extensive vascular invasion (now called encapsulated angioinvasive) (>4 foci) Widely invasive Poorly differentiated Anaplastic Group 2 (DTC on cytology or after core biopsy, who has not had prior thyroid surgery yet) Inclusion criteria Aged 16 or over 'low risk' differentiated thyroid cancer confirmed by cytology or core biopsy. cT1b-2 irrespective of molecular genetic markers cN0 Contralateral lobe without suspicious nodule(s) (U2, or U3/U4 with Thy2 on FNAC) Exclusion criteria • M1

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1: Two-stage Completion Thyroidectomy<br>Patients randomised to this arm will undergo a 2nd operation to remove the remaining thyroid lobe. | Procedure: Total Thyroidectomy<br>* Total Thyroidectomy - surgical removal of entire thyroid gland<br>|
| No Intervention: Group 1: Surveillance<br>Patients randomised to this arm will have no 2nd surgery and proceed directly to follow-up visits. | |
| Experimental: Group 2: Hemi-thyroidectomy<br>Patients randomised to this arm will have a single HT operation to remove thyroid lobe with the tumour. | Procedure: Hemithyroidectomy<br>* Hemithyroidectomy - surgical removal of partial thyroid gland<br>|
| Active Comparator: Group 2: Total Thyroidectomy<br>Patients randomised to this arm will have a single TT operation to remove the entire thyroid gland. | Procedure: Total Thyroidectomy<br>* Total Thyroidectomy - surgical removal of entire thyroid gland<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3 Year Recurrence Rate | (defined as thyroid cancer recurrence, metastatic disease or death from thyroid cancer (whichever occurs first)) | From surgery to any signs or symptoms of the cancer or death assessed up to a maximum of 3 years from surgery date | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5 Year Recurrence Rate | (defined as thyroid cancer recurrence, metastatic disease or death from thyroid cancer (whichever occurs first)) | From surgery to any signs or symptoms of the cancer or death assessed up to a maximum of 5 years from surgery date | 
| Anatomical Site of Recurrence | Location of recurrence | From surgery to confirmed recurrence assessed up to a maximum of 5 years from surgery date | 
| Risk of Loco-Regional Recurrence | (based on time to recurrence in the neck only) | From surgery to confirmed recurrence assessed up to a maximum of 5 years from surgery date | 
| Number of Additional Investigations and Procedures after Surgery | Number of further investigations/procedures related to the patient's thyroid surgery or thyroid cancer e.g. imaging, blood test, biopsy etc. | 2-4 weeks and 6, 18, 30, 42, 54, 66 and 78 months from date of surgery | 
| Type of Additional Investigations and Procedures after Surgery | Type of further investigations/procedures related to the patient's thyroid surgery or thyroid cancer e.g. imaging, blood test, biopsy etc. | 2-4 weeks and 6, 18, 30, 42, 54, 66 and 78 months from date of surgery | 
| Voice Function | Measured using the Voice Handicap Index questionnaire (VHI-10); scores range from 0-40 with higher scores indicating greater voice-related handicap | Surgical complications and severity: From surgery date to discharge, 2-4 weeks, 6 months and 18 months from date of surgery; Voice Function: Post-randomisation/pre-surgery, 2-4 weeks and 6, 18, 30, 42, 54, 66 and 78 months from date of surgery. | 
| Surgical complications and severity | Using CTCAE v5.0 and the highest grade of each event type for each patient | Surgical complications and severity: From surgery date to discharge, 2-4 weeks, 6 months and 18 months from date of surgery; Voice Function: Post-randomisation/pre-surgery, 2-4 weeks and 6, 18, 30, 42, 54, 66 and 78 months from date of surgery. | 
| Requirement for Hormone Replacement Therapy | (percentage of patients who require this therapy compared between the trial arms) | From surgery date to discharge, 2-4 weeks and 6, 18, 30, 42, 54, 66 and 78 months from date of surgery. | 
| Health Related Quality of Life | Measured using EORTC QLQ-C30; Scales range from 0-100 with higher scores for the functioning scales and global health status indicating higher QoL and higher scores on the symptom and single-item scales indicating lower QoL | Baseline (post-randomisation/pre-surgery), 2-4 weeks and 6, 18, 30, 42, 54, 66 and 78 months from date of surgery. | 
| Health Related Quality of Life | Measured using EORTC QLQ-THY35; Scales range from 0-100 with higher scores indicating higher QoL and lower scores indicating lower QoL | Baseline (post-randomisation/pre-surgery), 2-4 weeks and 6, 18, 30, 42, 54, 66 and 78 months from date of surgery. | 
| Health Related Quality of Life | Measured using EQ5D-5L; EQVAS score ranges from 0-100 with higher scores indicating higher QoL and lower scores indicating lower QoL; EQ-5D-5L index scores range from -0.224-1 with higher scores indicating higher QoL and lower scores indicating lower QoL | Baseline (post-randomisation/pre-surgery), 2-4 weeks and 6, 18, 30, 42, 54, 66 and 78 months from date of surgery. | 
| Health Related Quality of Life | Measured using FoP-Q-SF; scores range from 12-60 with higher scores indicating lower QoL and lower scores indicating higher QoL | Baseline (post-randomisation/pre-surgery), 2-4 weeks and 6, 18, 30, 42, 54, 66 and 78 months from date of surgery. | 
| Cost and Health Resource Use | Measured using EQ-5D-5L (generic QoL) | a. Baseline, 2-4 weeks and 6, 18, 30, 42, 54, 66 & 78 months from date of surgery. b. From surgery date to discharge, 2-4 weeks and 6, 18, 30, 42, 54, 66 & 78 months from date of surgery. c/d. 6, 18, 30, 42, 54, 66 & 78 months from date of surgery | 
| Cost and Health Resource Use | Measured using EORTC QLQ-C30 (cancer-specific QoL) | a. Baseline, 2-4 weeks and 6, 18, 30, 42, 54, 66 & 78 months from date of surgery. b. From surgery date to discharge, 2-4 weeks and 6, 18, 30, 42, 54, 66 & 78 months from date of surgery. c/d. 6, 18, 30, 42, 54, 66 & 78 months from date of surgery | 
| Cost and Health Resource Use | Measured using EORTC QLQ-THY34 (Cancer site specific QoL) | a. Baseline, 2-4 weeks and 6, 18, 30, 42, 54, 66 & 78 months from date of surgery. b. From surgery date to discharge, 2-4 weeks and 6, 18, 30, 42, 54, 66 & 78 months from date of surgery. c/d. 6, 18, 30, 42, 54, 66 & 78 months from date of surgery | 
| Secondary Care Health Resource Use | Collected using eCRFs and retrospectively for the study period from data in the Hospital Episodes Statistics linked to records in the NCRAS | a. Baseline, 2-4 weeks and 6, 18, 30, 42, 54, 66 & 78 months from date of surgery. b. From surgery date to discharge, 2-4 weeks and 6, 18, 30, 42, 54, 66 & 78 months from date of surgery. c/d. 6, 18, 30, 42, 54, 66 & 78 months from date of surgery | 
| Primary Care Health Resource Use | Collected using eCRFs (Review of Primary Care Visits) | a. Baseline, 2-4 weeks and 6, 18, 30, 42, 54, 66 & 78 months from date of surgery. b. From surgery date to discharge, 2-4 weeks and 6, 18, 30, 42, 54, 66 & 78 months from date of surgery. c/d. 6, 18, 30, 42, 54, 66 & 78 months from date of surgery |