Clinical trialPhase 3Thyroid cancer

Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer

N Engl J Med · 2022776 patients randomised (ClinicalTrials.gov); 730 patients evaluable at 3 years

Leboulleux S, Bournaud C, Chougnet CN, et al. N Engl J Med. 2022. 386:923-932

Study type: Clinical trial
Study name: ESTIMABL2
Phase: Phase 3
Design: Prospective, randomised, multicentre non-inferiority trial in France; non-inferiority margin less than 5 percentage points
Sample size: 776 patients randomised (ClinicalTrials.gov); 730 patients evaluable at 3 years
Source: N Engl J Med · 2022
Trial registration: NCT01837745

In plain words

After surgery to remove the thyroid, many patients have traditionally been given radioactive iodine. This French trial showed that in low-risk thyroid cancer, skipping radioactive iodine and having regular check-ups with ultrasound and a blood test (thyroglobulin) is just as safe: after 3 years, about 96 out of every 100 patients in both groups had no sign of disease. This means many low-risk patients can be spared the side effects and hassle of radioactive iodine. The final decision depends on the features of your tumour and should be made with your treating doctor.

Key results

95.6% (no radioiodine) vs 95.9% (radioiodine)

Patients without an event at 3 years

95% CI 93.0-97.5 vs 93.3-97.7

-0.3 percentage points

Difference between the two groups

two-sided 90% CI -2.7 to 2.2; non-inferiority criterion met

Structural or functional abnormalities in 8 patients; biological abnormalities in 23 patients (25 events)

Events

Events were more frequent in patients with postoperative thyroglobulin above 1 ng/mL

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

1Radioiodine group (ablation)

Thyrotropin alfa (rhTSH, recombinant human thyrotropin) 0.9 mg by intramuscular injection on two consecutive days while the patient continued levothyroxine (no hormone withdrawal); then iodine-131 with an activity of 1.1 GBq (30 mCi) orally 24 hours after the second injection; whole-body scan 2 to 5 days after iodine administration with measurement of neck uptake. Follow-up: at 10 months after randomisation, neck ultrasound and rhTSH-stimulated thyroglobulin; then thyroglobulin on levothyroxine at years 2, 3, 4, 5, 8, 10 and 12 and neck ultrasound at years 3, 5, 8, 10 and 12. A low-iodine diet is not mentioned in the sources reviewed.

2No-radioiodine group (follow-up)

No iodine-131 and no rhTSH; the same follow-up schedule (neck ultrasound and serum thyroglobulin measurement), except that at month 10 thyroglobulin was measured on levothyroxine (not after rhTSH stimulation).

Source of the regimen details: ClinicalTrials.gov NCT01837745 (dose and timing of rhTSH, iodine-131 activity of 1.1 GBq [30 mCi], post-therapy scan and follow-up schedule) and the abstract of the paper; FDA label for thyrotropin alfa (THYROGEN, DailyMed): 0.9 mg intramuscularly into the buttock, with a second dose 24 hours later. The full NEJM text was not available in PMC; 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

Adults (18 years and older) with performance status 0 or 1 and low-risk differentiated thyroid cancer (papillary, follicular or Hürthle cell, without aggressive subtypes such as poorly differentiated, tall cell, columnar, diffuse sclerosing or an anaplastic component), 2 to 5 months after total thyroidectomy with complete tumour resection (R0), with or without lymph node dissection. Stage (TNM 2010): pT1am N0/Nx with a combined lesion size of more than 1 and at most 2 cm, or pT1b N0/Nx. On postoperative neck ultrasound there had to be no lateral lymph node with abnormal cytology or aspirate-fluid thyroglobulin above 10 ng/mL. Exclusion criteria: unifocal pT1a, pT1N1, pT2 to pT4, N1, distant metastasis, recent use of drugs affecting thyroid function, including injection of radiological contrast medium within the previous 8 weeks, and previous radioiodine treatment or scan. Patients with or without anti-thyroglobulin antibodies were eligible (criteria from ClinicalTrials.gov).

Endpoints

Primary objective: to assess the non-inferiority of a no-radioiodine strategy versus radioiodine treatment with respect to the absence of a composite endpoint of functional, structural and biological abnormalities at 3 years (abnormal foci of iodine uptake on whole-body scan requiring further treatment [radioiodine group only], abnormal neck ultrasound findings, or elevated thyroglobulin or anti-thyroglobulin antibodies). Secondary endpoints: prognostic factors for events and molecular characteristics.

Safety and side effects

No treatment-related adverse events were reported.

Clinical significance and place in guidelines

The 2025 American Thyroid Association (ATA) guideline cites ESTIMABL2 and recommends that remnant ablation after total thyroidectomy should not be performed routinely in ATA low-risk patients (strong recommendation, high-certainty evidence). Together with the IoN trial, this study is the main basis for omitting routine radioiodine in low-risk differentiated thyroid cancer.

Limitations

The follow-up of the main report (3 years) is relatively short for a very slow-growing cancer (the 2025 ATA guideline also notes this limitation). The primary endpoint was composite, and most events were biological abnormalities (thyroglobulin/antibodies) rather than structural recurrence. Only very low-risk patients (mostly pT1 tumours without nodal involvement) were enrolled.

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.