Clinical trialPhase 3Thyroid cancer

Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer

N Engl J Med · 2012438 patients randomised; 421 patients evaluable

Mallick U, Harmer C, Yap B, et al. N Engl J Med. 2012. 366:1674-1685

Study type: Clinical trial
Study name: HiLo
Phase: Phase 3
Design: Randomised non-inferiority trial with a 2×2 factorial design at 29 centres in the UK: low-dose versus high-dose radioiodine, each with thyrotropin alfa or thyroid hormone withdrawal
Sample size: 438 patients randomised; 421 patients evaluable
Source: N Engl J Med · 2012
Trial registration: NCT00415233

In plain words

If radioactive iodine is needed after thyroid surgery, this UK trial showed that a low dose (1.1 gigabecquerels) is as effective as a high dose (3.7 gigabecquerels) at destroying the thyroid tissue left behind, but with fewer side effects and a shorter hospital stay. Preparation with injections of man-made TSH hormone (thyrotropin alfa) also worked as well as the old method of stopping thyroid tablets, and it spares the patient the symptoms of a severely underactive thyroid during the weeks off the tablets.

Key results

85.0% vs 88.9%

Ablation success: low dose vs high dose

All 95% CIs for the differences within ±10 percentage points (non-inferiority)

87.1% vs 86.7%

Ablation success: thyrotropin alfa vs hormone withdrawal

Non-inferiority

36.3% vs 13.0%

Hospital stay of at least 3 days: high dose vs low dose

P<0.001

21% vs 33%

Patients with an adverse event: low dose vs high dose

P=0.007

7 years: 5.9% vs 7.3% (3 years: 1.5% vs 2.1%; 5 years: 2.1% vs 2.7%)

Recurrence in long-term follow-up: low dose vs high dose

HR 1.10; 95% CI 0.47–2.59; P=0.83; median follow-up 6.5 years; rhTSH vs hormone withdrawal at 7 years: 8.3% vs 5.0% (HR 1.62; 95% CI 0.67–3.91; P=0.28); Dehbi et al., Lancet Diabetes Endocrinol 2019

Dose and schedule cards

Low-activity iodine-131 after thyrotropin alfa (HiLo, ESTIMABL2, IoN)

After total (or near-total) thyroidectomy for differentiated thyroid cancer, only when radioiodine is indicated; not routinely recommended in low risk and “may be considered” in low-intermediate and intermediate-high risk; no distant metastasesOn the page “Thyroid cancer” · Radioactive iodine: activity and preparation

Drug	Dose	Route	Schedule
Preparation (preferred by the ATA guideline)
Thyrotropin alfa (recombinant TSH)	0.9 mg	IM (buttock); never IV	Day 1 and day 2 (24 hours apart)
Alternative preparation: hormone withdrawal (HiLo protocol)
Withdrawal of liothyronine (T3) or levothyroxine (T4)	Stop T3 for 2 weeks, or T4 for 4 weeks	—	Before radioiodine
Ablation
Iodine-131	1.1 GBq (about 30 mCi)	Oral	24 hours after the second thyrotropin alfa injection (or after the hormone withdrawal period)

Cycle length: Single administration
Duration: Single dose

Sources: thyrotropin alfa FDA label (dose and schedule; the radioiodine activity is chosen by the nuclear medicine physician); HiLo; ESTIMABL2. In HiLo (ablation 1 to 6 months after surgery), 1.1 GBq was noninferior to 3.7 GBq (about 100 mCi), and the two preparation methods (thyrotropin alfa or thyroid hormone withdrawal) gave similar results. In the HiLo hormone-withdrawal group, most patients stopped liothyronine (mean 60 mcg per day) 2 weeks before ablation, and a small number stopped levothyroxine (mean 200 mcg per day) 4 weeks before ablation. In patients in whom tumour growth after TSH stimulation could compress vital structures, consider pretreatment with a glucocorticoid.

On the page “Thyroid cancer” · Radioactive iodine: activity and preparation

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Low-dose radioiodine + thyrotropin alfa

Thyroid hormone continued; thyrotropin alfa (rhTSH, Thyrogen) 0.9 mg intramuscular injection on day 1 and day 2 (that is, on each of the two days before treatment), then I-131 at an activity of 1.1 GBq (30 mCi) on day 3. Ablation was performed 1 to 6 months after surgery, and discharge from isolation followed a satisfactory radiation risk assessment.

2Low-dose radioiodine + thyroid hormone withdrawal

Thyroid hormone withdrawn before treatment: thyroxine (T4) was stopped 4 weeks before ablation, or triiodothyronine (T3, liothyronine) 2 weeks before (patients on T4 could be switched to T3 for 2 weeks before withdrawal; some centres did not start hormone replacement after surgery). In practice, across the withdrawal groups, 204 patients stopped T3 (mean 60 micrograms a day) for 2 weeks and 11 patients stopped T4 (mean 200 micrograms a day) for 4 weeks. Then I-131 at an activity of 1.1 GBq (30 mCi), 1 to 6 months after surgery.

3High-dose radioiodine + thyrotropin alfa

Thyroid hormone continued; thyrotropin alfa (rhTSH, Thyrogen) 0.9 mg intramuscular injection on day 1 and day 2 (that is, on each of the two days before treatment), then I-131 at an activity of 3.7 GBq (100 mCi) on day 3. Ablation was performed 1 to 6 months after surgery, and discharge from isolation followed a satisfactory radiation risk assessment.

4High-dose radioiodine + thyroid hormone withdrawal

Source of the regimen details: ClinicalTrials.gov NCT00415233 (rhTSH 0.9 mg intramuscularly on days 1 and 2 and iodine on day 3; T4 withdrawn four weeks or T3 two weeks before treatment); full text of the long-term HiLo report in PMC (Lancet Diabetes Endocrinol 2019, PMC6299255: mean T4 and T3 doses, number of patients with each method and timing of treatment 1 to 6 months after surgery); abstract of the NEJM paper (activities of 1.1 GBq [30 mCi] and 3.7 GBq [100 mCi]). Note: the ClinicalTrials.gov page gives the high activity as 3.2 GBq, but the published papers report 3.7 GBq. A low-iodine diet is not mentioned in these sources.

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 16 to 80 years with differentiated thyroid cancer (T1 to T3, Nx/N0/N1, no distant metastases) who had undergone one-stage or two-stage total thyroidectomy with or without lymph node dissection and complete tumour resection (R0) and were scheduled for thyroid remnant ablation; WHO performance status 0 to 2. Exclusion criteria: Hürthle cell carcinoma or aggressive subtypes (tall cell, insular, poorly differentiated, diffuse sclerosing), anaplastic or medullary carcinoma, contrast-enhanced CT within the past 3 months, a prior I-131 or I-123 scan before treatment, prior treatment for thyroid cancer other than surgery, and pregnancy or breastfeeding. Contraception was required for 6 months (women) and 4 months (men) after treatment (criteria from ClinicalTrials.gov).

Endpoints

Ablation success rate at 6 to 9 months, adverse events, quality of life and length of hospital stay.

Safety and side effects

The proportion of patients with an adverse event was 21% in the low-dose group versus 33% in the high-dose group (P=0.007), and 23% in the thyrotropin alfa group versus 30% in the thyroid hormone withdrawal group (P=0.11). A hospital stay of 3 days or more was more common in the high-dose group (36.3% versus 13.0%).

Clinical significance and place in guidelines

The 2025 American Thyroid Association (ATA) guideline, citing HiLo (and its long-term follow-up with a median of 6.5 years, which showed similar recurrence rates with the low and high doses), states that in the selected cases in which radioiodine is used in low-risk patients, a low dose of 1.1 to 1.85 GBq (30 to 50 mCi) should be given. The guideline also prefers preparation with rhTSH over thyroid hormone withdrawal (strong recommendation, high-certainty evidence).

Limitations

The primary endpoint was ablation success at 6 to 9 months (a surrogate endpoint), not recurrence or survival; recurrence data were published in later follow-up. Patients were mainly at low or intermediate risk, and the results cannot be generalised to high-risk patients. The design was open-label (not blinded).

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.