A safer and shorter treatment for thyroid cancer
Submitting InstitutionUniversity College London
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences, Oncology and Carcinogenesis
Summary of the impact
The HiLo trial has changed management for patients with
well-differentiated thyroid cancer. Patients undergoing radioiodine
ablation therapy are now given a low dose of radioactive iodine, which has
fewer side effects, compared to the previous (standard) high dose. Also,
to prepare patients for ablation they now have recombinant human TSH
(thyrotropin alfa), which is associated with a better quality of life
before and during ablation. The combination of low dose radioiodine and
thyrotropin alfa means that patients can be treated as outpatients rather
than inpatients. This is a more convenient treatment package, reducing
health service and societal costs.
Prior to the research described below, the standard treatment for most
patients with well-differentiated thyroid cancer was as follows: they
would first have a total thyroidectomy, then would go on lifelong thyroid
hormone suppression therapy (THST); several weeks later they would receive
high dose (3.7 GBq) radioactive iodine to destroy remaining cancer cells
or residual normal thyroid tissue, at which point they would spend two to
five days in hospital isolation, because of radiation protection issues;
before radioiodine ablation, patients would have to temporarily stop THST,
which would result in hypothyroidism, reducing quality of life.
There were two unanswered questions about this treatment, which our
research aimed to address. Firstly, high dose radioiodine has side effects
and increases the chance of a new cancer in the future, and there has long
been discussion over whether low dose radioiodine is just as effective.
Secondly, a longstanding research question was whether taking recombinant
human thyroid stimulating hormone (thyrotropin alfa) before ablation
(which avoids the need to stop THST) would affect treatment success rates.
In 2007, Professor Allan Hackshaw (Cancer Research UK and UCL Cancer
Trials Centre) initiated and led a comprehensive systematic review of all
59 published studies into thyroid cancer, in order to address these two
questions. This evaluation showed that it was not possible to reliably
determine whether clinicians could use a lower radioiodine dose or not,
and there was insufficient evidence to recommend thyrotropin alfa before
As a result of these findings, Cancer Research UK (CRUK) funded a large
randomised trial, led by Hackshaw and the trial Chief Investigator, Dr
Ujjal Mallick (Freeman Hospital, Newcastle). The trial concept originated
from Mallick and Hackshaw through the NCRN Head and Neck Cancer Clinical
Studies Group. UCL was responsible for trial design, study conduct and
statistical analyses, and was the trial Sponsor.
HiLo was the first ever UK national trial in thyroid cancer (438 patients
recruited 2007-10), and the first factorial study in this cancer. It was
independently peer-reviewed by CRUK, conducted across the UK National
Cancer Research Networks and published in the New England Journal of
Medicine . These attributes confirm the high quality of this
seminal and unique trial.
Treatment success rates were 85.0% in the group receiving low-dose
radioiodine versus 88.9% in the group receiving the high dose; and 87.1%
in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid
hormone withdrawal — all indicating non-inferiority. Similar results were
found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus
high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose
radioiodine plus thyrotropin alfa (90.2%).
References to the research
 Hackshaw AK, Harmer C, Mallick U, Haq M, Franklyn J. 131I activity
for remnant ablation in patients with differentiated thyroid cancer: a
systematic review. J Clin Endocrin Metab 2007; 92(1): 28-38 http://dx.doi.org/10.1210/jc.2006-1345
 Mallick U, Harmer C, Yap B, Wadsley J, Clarke S, Moss L, Nicol A,
Clark PM, Farnell K, McCready R, Smellie J, Franklyn JA, John R, Nutting
CM, Newbold K, Lemon C, Gerrard G, Abdel-Hamid A, Hardman J, Macias E,
Roques T, Whitaker S, Vijayan R, Alvarez P, Beare S, Forsyth S, Kadalayil
L, Hackshaw A. Ablation with low-dose radioiodine and thyrotropin alfa in
thyroid cancer. N Engl J Med. 2012 May 3;366(18):1674-85. http://dx.doi.org/10.1056/NEJMoa1109589
Funding: Cancer Research UK (2007-2010)
Title: Randomised trial of low and high dose radioiodine, with or
without, recombinant human thyroid stimulating hormone, in treating
Applicants: U Mallick (Freeman Hospital, Newcastle), A Hackshaw (UCL), C
Harmer (Royal Marsden Hospital)
Sponsor: University College London
Details of the impact
There are >2,100 new cases of thyroid cancer each year in the UK,
>48,000 in the US, and >213,000 worldwide. It is the most frequently
occurring endocrine tumour, and one of the few cancers where the incidence
is increasing [a]. Thyroid cancer, unlike most other cancers, is
common among younger people (<50 years) who are still in work, and
particularly women (many with children). Most cases are
well-differentiated thyroid cancer (85-90% of new cases), in which the
cure rate is already high; therefore new treatments that are safer,
cheaper or easier to administer are the research goals.
The results of the HiLo trial provided clear evidence for a shorter and
safer treatment for thyroid cancer. Cancer Research UK commented that the
results of this trial "have set a new gold standard for treating
thyroid cancer, reducing radiation doses to just one third of the
current level... patients taking the lower dose capsule can be treated
more easily as an outpatient in hours and experience fewer side effects"
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. Overall, the research described above showed the following
benefits to patients and to the economy:
Benefits to patients:
- New treatment can be delivered as outpatient treatment which is
quicker and easier for patient
- 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
- Improved quality of life, as THST 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)
- Reduction in side effects is associated with lower costs to treat
these side effects.
- Shorter hospital stay also reduces costs
- Overall 14% reduction in NHS costs using low dose radioiodine plus
thyrotropin alfa 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 during the 2-4 weeks before radioiodine
treatment is 1 day (low dose) compared to 5 days (high dose).
We have disseminated the results of the HiLo trial through presentations
at several international conferences in countries planning to change
routine practice (including Europe, Israel and Korea) [c]. Our
results were also widely reported in the medical press and in
patient-facing resources on thyroid cancer treatment [d].
In 2012, the trial findings were used to change the European licence
indication for Thyrogen (thyrotropin alfa), so that it can now be used
with low dose radioiodine (the previous licence was only for use with the
high dose) [e].
New guidelines are currently in preparation in both the UK [f]
and US [g] to recommend low dose radioactive iodine and
thyrotropin alfa for routine practice. In the meantime, this treatment.is
already being adopted; the NCRI Clinical Studies Groups 2013 annual
report, impact section, states: "The HiLO study published in the New
England Journal of Medicine is now significantly changing the clinical
practice of oncologists and endocrinologists giving post-operative
radio-iodine ablation to thyroid cancer patients. The dose has now been
decreased considerably as a result of this study and adoption has
proceeded rapidly in the UK" [h].
An informal survey of clinicians has shown that 16 centres in the UK have
implemented the HiLo trial protocols since the publication. Responses
"I am routinely using HILO doses as per study in my practice ever
since results were confirmed."
"Our policy...is to stratify patients needed I131 post thyroidectomy
who would have fit the criteria for the Hi-Lo into 2 groups low risk or
higher risk. Those patients in who remnant ablation is the aim of
management (i.e. well differentiated node negative disease T1-3) are
considered low risk and are treated with Thyrogen priming pre ablation
and 1.1 GBq I131 as HiLo study" [i].
"We have been using lower activity RAI for about 18 months" [j].
"I can confirm that I have implemented one element of the HiLo study
before 31/7/2013...Specifically this is the lower dose of I131" [k].
Following on from the HiLo trial, a new trial — ION — is underway to
determine whether thyroid cancer patients, in whom the risk of the cancer
coming back is low, need radioactive iodine (RAI) ablation at all, given
that they have already had a total thyroidectomy and are being given
thyroid stimulating hormone suppression (TSHS) therapy [l]. The
control arm for this trial uses low dose radioactive iodine, demonstrating
that this is now entering accepted standard practice in the 35 centres
participating in the trial.
Sources to corroborate the impact
[a] Cancer Research UK. Thyroid cancer statistics, UK: http://info.cancerresearchuk.org/cancerstats/types/thyroid
National Cancer Institute. Thyroid cancer, US: http://www.cancer.gov/cancertopics/types/thyroid
[b] press release http://www.cancerresearchuk.org/cancer-info/news/archive/pressrelease/2012-05-02-thyroid-cancer-trial-results
[c] Weblinks to international presentations of HiLo
[d] Reporting of our trial results:
[e] European Medicines Agency (EMEA) revised license for Thyrogen, Oct
[f] Corroboration is available from the UK lead. Contact details
[g] Corroboration is available from the US lead. Contact details
[h] NCRI Head & Neck Cancer Clinical Studies Group 2012/13 annual
report, impact section. http://www.ncri.org.uk/csg/annual_reports/NCRI_Head_&_Neck_CSG_-_Annual_Report.pdf
[i] Correspondence from Clinical Director, Oncology, The Royal
Wolverhampton NHS Trust. Available on request.
[j] Correspondence from Consultant Clinical Oncologist, Beatson Oncology
Centre, Glasgow. Available on request.
[k] Correspondence from Divisional Clinical Director, The Ipswich
Hospital NHS Trust. Available on request.