MR1090 - HiLo: Multicentre randomised trial of high dose versus low dose radioiodine

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement for an interim period in which University College London (UCL) must complete the necessary actions to enable a subsequent application to extend the Agreement meeting all applicable data sharing standards as published in NHS Digital’s website (see: https://digital.nhs.uk/services/data-access-request-service-dars/dars-guidance).

Data held by UCL must be securely stored and not otherwise processed.

The following provides background information on the purpose of the original study:

Mortality and Cancer data were supplied to Cancer Research UK and UK Cancer Trials Centre, UCL by ONS and subsequently the Health and Social Care Information Centre (now known as NHS Digital) for the purpose of a research study referred to as 'HiLo: Multicentre randomised trial of high dose versus low dose radioiodine'

The original objectives of the HiLo trial were to explore whether giving a lower dose of radioiodine ablation (1.1 GBq) was as effective as the ‘standard’ dose (3.7 GBq) in treating patients with differentiated thyroid cancer, in terms of reducing local/distant recurrence and death from thyroid cancer. The trial also investigated whether these effects were influenced by using either recombinant thyroid stimulating hormone (rhTSH) or thyroid hormone withdrawal.

A total of 438 patients were randomised to the trial (Jan 2007 – Jul 2010) and safety and efficacy data were published in 2012 (Mallick et al., Ablation with Low-Dose Radioiodine and Thyrotropin-alfa in Thyroid Cancer, New Engl J Med 2012; 366:1674-85).

The results showed that there are similar rates of thyroid-remnant ablation, without evidence of residual disease after surgery, for pre-treatment with either 1.1-GBq or 3.7-GBq 131I, plus or minus thyrotropin-alfa. Thus lower dose radioiodine (1.1 GBq), with thyrotropin-alfa or thyroid hormone withdrawal, is as effective as high dose (3.7-GBq) treatment for patients with low and intermediate risk differentiated thyroid cancer. The reduction in irradiation had the benefit of a shorter period of isolation in hospital following treatment, and patients experienced fewer adverse events during and for up to 3 months after ablation, hence improving quality of life, and, incidentally, reducing healthcare and societal costs.

This changed clinical practice and 1.1 GBq has now become standard of care for this population of patients, as recommended in the 2014 British Thyroid Association (BTA) guidelines.

Long-term follow up results for the trial were published in 2017 (Dehbi et al., 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, Lancet Diabetes Endocrinol 2019; 7(1):44-5).

These results showed that after a median follow up of 6.5 years 21 patients had confirmed recurrence (11 who had 1.1 GBq ablation and 10 who had 3.7 GBq ablation), and was not affected by whether patients had rhTSH or hormone withdrawal prior to ablation. Cumulative recurrence rates at 3 years (1.5% vs 2.1%), 5 years (2.1% vs 2.7%) and 7 years (5.9% vs 7.3%) were similar between low-dose and high-dose radioactive iodine groups.

This provides further evidence for the use of 1.1 GBq as standard of care for this population of patients.

The objective for receiving more data from NHS Digital is to provide further evidence for the results seen so far. The publication from 2017 had a median follow up of 6.5 years, so a further long term follow up paper is planned, once median follow up is between 10 and 15 years. At this time data on new malignancies and deaths would be included.

This trial remains active (protocol version 1.8, 10/07/2020) as follow up data is still being collected from hospital sites where patients are still being followed up. Many patients are discharged from hospital follow up after a number of years (5-10), and it is these patients that we are particularly interested in receiving data for from NHS Digitals, as it may not be possible to obtain data on new malignancies and/or death from the hospital.

These additional results, where applicable, may be included in any future updates in BTA guideline.

Under this Agreement, the data may be securely stored but not otherwise processed. No new data will be provided by NHS Digital under this Agreement.

The study data, including data provided by NHS Digital under previous versions of this Agreement, are currently held by UCL. Under this interim extension all devices containing data will be securely locked away in a locked cabinet at the UCL storage address specified in this Agreement.

The following provides background on the processing activities undertaken for the original study:

Identifiable data was shared with ONS to carry out the linkage between the study data and civil registration data. Participants records were ‘flagged’ with the Office for National Statistics (ONS). ONS notified the study team at UCL of participants’ deaths (date and cause) and cancer events when they occurred. The ‘flagging for long-term follow up’ service transferred from ONS to the HSCIC in 2008. Data was last supplied in June 2017.

New outputs are being requested on the data already flagged, to fulfil the objectives stated in section 5a above. Data were previously received every 3 months, but as the numbers received are low it is proposed bi-annual data outputs would be acceptable. In addition, there may be scope for data minimisation – patient trial number, patient initials, and data of birth would be adequate to ensure correct linkage of patients at CTC.

This Agreement permits the secure retention of the data only and no other processing. No new outputs will be produced under this Data Sharing Agreement.

A further publication on long term follow up is planned, once median follow up is between 10 and 15 years. This will provide further updates on recurrences, and data on new primary cancers and deaths (some of which may be obtained from NHS Digital) will be included.

It is anticipated the numbers of new malignancies and deaths received from NHS Digital will continue to be low, which will provide evidence on the safety of this treatment for this population of patients.

It is anticipated these additional results will provide further evidence for the use of 1.1 GBq as standard of care for this population of patients. Guidelines (e.g. the BTA guidelines) could also be strengthened on the basis of the evidence.

This Agreement permits the secure retention of the data only and no other processing.

In any future application, the applicant will be required to provide details of the expected benefits resulting from the study.

In terms of benefits to Health and/or Social Care it is expected that the evidence provided from updated long term follow up of this trial (including new malignancies and deaths) will further assure patients and clinicians of the benefits of using low dose (1.1 GBq) in this patient population.

Safety and efficacy data for the trial were published in 2012 (Mallick et al., Ablation with Low-Dose Radioiodine and Thyrotropin-alfa in Thyroid Cancer, New Engl J Med 2012; 366:1674-85).

The results showed that there are similar rates of thyroid-remnant ablation, without evidence of residual disease after surgery, for pre-treatment with either 1.1-GBq or 3.7-GBq 131I, plus or minus thyrotropin-alfa. Thus lower dose radioiodine (1.1 GBq), with thyrotropin-alfa or thyroid hormone withdrawal, is as effective as high dose (3.7-GBq) treatment for patients with low and intermediate risk differentiated thyroid cancer. The reduction in irradiation had the benefit of a shorter period of isolation in hospital following treatment, and patients experienced fewer adverse events during and for up to 3 months after ablation, hence improving quality of life, and, incidentally, reducing healthcare and societal costs.

This changed clinical practice and 1.1 GBq has now become standard of care for this population of patients, as recommended in the 2014 British Thyroid Association (BTA) guidelines.

Long-term follow up results for the trial were published in 2017 (Dehbi et al., 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, Lancet Diabetes Endocrinol 2019; 7(1):44-5).

These results showed that after a median follow up of 6.5 years 21 patients had confirmed recurrence (11 who had 1.1 GBq ablation and 10 who had 3.7 GBq ablation), and was not affected by whether patients had rhTSH or hormone withdrawal prior to ablation. Cumulative recurrence rates at 3 years (1.5% vs 2.1%), 5 years (2.1% vs 2.7%) and 7 years (5.9% vs 7.3%) were similar between low-dose and high-dose radioactive iodine groups.

This provides further evidence for the use of 1.1 GBq as standard of care for this population of patients.