HiLo trial - impact case study

There are around 3,500 newly diagnosed patients with thyroid cancer each year in the UK (CRUK 2015 figures).

Papillary and follicular thyroid cancers are referred to as differentiated thyroid cancer. Differentiated thyroid cancer is the most common type of thyroid cancer, with a survival rate of over 90 per cent at ten years.

Most cases are cured with a combination of surgery to remove the thyroid and, apart from those that are very low risk, radioiodine to destroy any residual cells.

Prior to this study the usual activity of radioiodine given was 3.7GBq. Some studies had reported that a lower activity of radioiodine works as well as the standard higher activity. If so, this reduction in activity would reduce side effects and potentially longer term risks for patients.

After surgery to remove thyroid cancer, patients need to take thyroid hormone tablets to replace the hormones their thyroid gland would normally make. Previously patients had to stop taking these tablets from around two-four weeks before having radioiodine to allow the levels of another hormone, Thyroiod Stimulating Hormone (TSH) to rise. This is necessary to ensure maximal efficacy of radioiodine therapy but which leads to patients suffering debilitating symptoms, such as feeling tired, depressed and gaining weight.

The use of an injection called recombinant human thyroid stimulating hormone (rhTSH) for two days before the start of radioiodine treatment is an alternative method of raising TSH levels prior to therapy. This means that patients don’t have to stop taking thyroid hormones and thus the symptoms of hypothyroidism are prevented.

However, it was previously unclear whether ablation success rates could be adversely affected by recombinant human thyroid stimulating hormone when giving radiodine therapy.

The primary aim of the HiLo trial was to compare the rate of success of thyroid remnant ablation in low and intermediate risk differentiated thyroid cancer patients receiving high (3.7GBq) dose versus low (1.1GBq) dose radioiodine, each with and without recombinant thyroid stimulating hormone. A later analysis after longer follow up assessed whether there was any difference in thyroid cancer recurrence between the groups in the study, and the results showed that using 1.1GBq did not lead to higher recurrence rates than 3.7GBq.

438 patients with well-differentiated thyroid cancer were recruited and randomised into one of four groups from 31 UK centres. Patients received a follow up scan six-nine months post treatment. Second malignancies were recorded separately.

Key features

• Chief Investigator: Dr Ujjal Mallick, The Newcastle upon Tyne Hospitals NHS Foundation Trust

• 8 November 2006 to 1 July 2010

• 438 participants were recruited from 31 sites across the UK involving 12 Local Clinical Research Networks and one Devolved Nation

• Funded by: Cancer Research UK

Outcomes and findings

Following publication of the HiLo trial in the New England Journal of Medicine, national and international guidelines have now changed to recommend the low dose and that patients can be prepared for ablation using rhTSH; and both are now established standards of care.

Also, the European licence indication for rhTSH (called Thyrogen), was changed to allow it to be used with low dose radioiodine (the previous licence was only for use with the high dose). When the licence was changed, the European Medicines Agency asked for future data on recurrence, which has now been provided to them, which gives no cause for concern.

The HiLo trial collected data on clinical efficacy, patient safety/harms, NHS resource use, and societal costs, allowing a comprehensive assessment of the impact in the clinical setting, as well as on healthcare costs and people’s lives.

“The delivery of this trial in a relatively rare cancer is a major achievement for the UK thyroid cancer community. The findings have led to changes in national and international guidelines, resulting in less toxic and better tolerated treatment for this patient group. The thyroid cancer group continue to work on studies aiming to improve outcomes and reduce side effects for patients with thyroid cancer.”

Professor Jonathan Wadsley, NIHR Clinical Research Network
National Specialty Lead for Radiotherapy and Imaging

Benefits to patients

• Low dose ablation can be delivered as an outpatient treatment which is quicker and easier for patients.

• Fewer side effects (e.g. nausea and neck pain).

• Reduced chance of developing a new tumour in the next 10-30 years, which can often be more difficult to treat than the original thyroid cancer.

• Improved quality of life, as hormone replacement therapy does not need to be suspended (of particular relevance to those of working age, or caring for children – which is a relatively high proportion for this type of cancer).

Value to the NHS

• Reduction in side effects is associated with lower costs to treat these side effects.

• Shorter hospital stay reduces NHS costs.

• Overall 14 per cent reduction in NHS costs using low dose radioiodine plus Thyrogen compared to the previous standard of high dose plus thyroid hormone withdrawal.

• Many thyroid cancer patients are in employed work, and the average number of days taken off work is one day (low dose) compared to five days (high dose).

Key publications

• New England Journal of Medicine: Ablation with Low-Dose Radioiodine and Thyrotropin Alfa in Thyroid Cancer

• Lancet Diabetes Endocrinol: Recurrence after low-dose radioiodine ablation and recombinant human thyroid-stimulating hormone for differentiated thyroid cancer (HiLo): long-term results of an open-label, non-inferiority randomised controlled trial