Title: Hemithyroidectomy or Total-Thyroidectomy in ‘low-risk’ thyroid cancers (HoT trial)
Funder: Department of Health and Social Care

Abstract: Differentiated Thyroid cancer (DTC) is a tumour with rapidly increasing incidence. Two-thirds of cases are women, and unlike most other cancers, thyroid cancer commonly occurs in younger people. Most patients with DTC are diagnosed when the tumour is small and localised, so they have an excellent prognosis; about 7% have a cancer recurrence within 8 years, and >99% survive to 10 years._x000D_ _x000D_ Standard care has been total thyroidectomy (TT) which is the removal of the whole thyroid gland, followed by radioactive iodine (RAI) remnant ablation and lifelong thyroid hormone replacement therapy. Side effects of TT and RAI include voice problems, dry mouth and low calcium levels, in addition to requiring lifelong hormone replacement. Clinical guidelines in the UK and US in 2015 suggest that the less invasive procedure of hemithyroidectomy (HT), also called lobectomy, which is removal of half of the thyroid gland, may be adequate treatment for low risk DTC. Both procedures are now performed within the standard care setting, however, there has never been a randomised trial comparing them. The extent of thyroid surgery for low-risk disease is therefore controversial leading to uncertainty amongst clinicians, wide variability in the use of HT across the UK and internationally, and increased anxiety amongst patients who fear having a recurrence if they have HT._x000D_ _x000D_ There is a trend towards reducing the intensity of treatment of cancers with excellent prognosis such as DTC in which TT could represent over-treatment for most low risk patients. This issue is potentially avoided or reduced by using HT. However, HT may be associated with a higher rate of cancer recurrence, and the safety and cost-effectiveness of follow-up of these patients remains unclear. There is concern that surgeons are choosing HT when observational evidence is conflicting and with a complete lack of evidence from randomised trials. It is essential that these data are quantified, so that patients and surgeons can balance the benefits and harms._x000D_ _x000D_ The HoT trial is a randomised trial conducted in a national oncology setting. 456 patients diagnosed with low-risk DTC will be recruited from ~30 UK centres. They will be identified from two groups; (1) after already having had a HT for thyroid problems and randomly allocated to a second operation for TT or surveillance only, (2) following a diagnostic biopsy but no surgery performed yet and randomly allocated to have either TT or HT. Patients will be monitored for up to 6.5 years using ultrasound scans and thyroglobulin, which are standard and sensitive tests for detecting recurrences early. Other outcomes include patient acceptance of the randomisation, quality of life, surgical outcomes and complications, use of thyroid hormone replacement therapy, and resource use and cost-effectiveness of both surgical options to the NHS. The study would provide definitive evidence that the recurrence rate for HT is not materially higher than for TT, and has fewer side effects and lower expected healthcare costs. There is no other randomised study that has compared HT with TT using any of the following: recurrence and surgical morbidity, patient-reported outcomes, or health service costs. If we show that HT has an acceptable recurrence rate international guidelines will recommend HT as a standard. But if HT leads to unacceptable recurrence rates the guidelines would also be revised to firmly recommend TT in most cases and much more careful use of HT.

Lay abstract: Research question_x000D_ Are patients with low risk differentiated thyroid cancer being over-treated by having a total thyroidectomy such that hemithyroidectomy is sufficient, or should total thyroidectomy remain as standard of care?_x000D_ _x000D_ Background_x000D_ The incidence of well-differentiated thyroid cancer (DTC) is increasing faster than any other tumour. Surgery is the most important prognostic determinant in the management of DTC. The current standard of care is total thyroidectomy (TT) with post-operative RAI ablation for all DTC >1cm which has excellent prognosis: 10-year overall survival is 98-99%, and recurrence rate 7% by 8 years._x000D_ _x000D_ In recent years, some surgeons have started to use hemithyroidectomy (HT) for some patients but the current evidence base for HT consists only of observational studies. Comparison of outcomes between HT and TT will therefore be affected by bias and confounding. Differential interpretation and implementation of international guidelines by local clinical teams have resulted in variable practices and increased anxiety for patients. A randomised trial is required to compare HT with TT._x000D_ _x000D_ Aims and objectives_x000D_ Primary objective: To determine whether hemithyroidectomy (HT) is an acceptable and cost-effective surgical procedure compared to total thyroidectomy (TT) in low risk thyroid cancer._x000D_ Secondary objectives include: assessment of the anatomical site of recurrence, surgical morbidity, quality of life, and number and type of additional investigations and treatments._x000D_ _x000D_ Methods_x000D_ The HoT trial is a multi-site non-inferiority trial. 456 low-risk patients diagnosed with DTC will be recruited from two groups; _x000D_ Group 1 (have already had HT with histology) - randomised 1:1 to a second operation (two-stage TT) or to surveillance only._x000D_ Group 2 (DTC on cytology with no thyroid surgery yet) - randomised 1:1 to HT or a single-stage TT._x000D_ Patients will be followed-up 2-4 weeks post-operation, at 6 months, and then annually for 6.5 years for the main analysis and funding period (and longer using electronic registry data). Follow-up assessments will include neck ultrasound, routine bloods (thyroid function, Tg, TgAb, calcium), voice assessment, and quality of life questionnaires._x000D_ _x000D_ The primary outcome is 3 (and 5 year) recurrence rate, analysed as time-to-event data using Kaplan-Meier curves and Cox regression, i.e. time to recurrence. The primary analyses will be per protocol, and a secondary analysis by intention-to-treat._x000D_ The cost-effectiveness of HT will be evaluated from a health and social services perspective over a 30 month and a lifetime horizon, including quality of life using the EQ-5D-5L at baseline, post-surgery, 6 months and then annually._x000D_ _x000D_ Timelines for delivery_x000D_ The HoT trial is a 96 month project. Year 1 will be for trial set-up, obtaining approvals, and opening trial sites. Recruitment will be over a 4 year period incorporating an 18 month recruitment pilot phase._x000D_ _x000D_ Anticipated impact and dissemination_x000D_ Trial findings will be used to revise and update national and international recommendations for routine practice, including the UK (BTA, ENT-UK), Europe (ETA) and the United States (ATA)._x000D_ _x000D_ Trial results will be disseminated at national/international conferences and published in high impact factor peer-reviewed journals. Results will also be disseminated via Patients’ associations through newsletters, journals, and bulletins, and via Cancer Research UK and the BAETS.

Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS