Thyroidectomy with or without postoperative radioiodine for patients with low-risk differentiated thyroid cancer in the UK (IoN): a randomised, multicentre, non-inferiority trial
- Study type
- Clinical trial
- Study name
- IoN
- Phase
- Phase 3
- Design
- Multicentre randomised non-inferiority trial (33 cancer centres in the UK), 1:1 allocation by minimisation; non-inferiority margin 5 percentage points; registration: ISRCTN80416929, EudraCT 2011-000144-21
- Sample size
- 504 patients (251 without ablation, 253 with ablation)
- Source
- Lancet · 2025
- Trial registration
- NCT01398085
In plain words
This British trial looked at whether people with low-risk thyroid cancer really need radioactive iodine after their whole thyroid has been removed. After about 7 years of follow-up, in both groups about 97 out of every 100 patients had no return of the cancer at 5 years, and no meaningful difference was seen. So many patients with small or medium-sized tumours, with no spread to the lymph nodes and no high-risk features, can safely skip radioactive iodine, the hospital stay that goes with it and its side effects. Your doctor will decide whether you need this treatment based on the pathology report of your tumour.
Key results
Treatment arms and regimens
Iodine-131 at a preferred activity of 1.1 GBq (about 30 mCi) after thyroidectomy; the protocol allowed centres to choose the activity (230 of 231 treated patients received about 1.1 GBq [range 1.02–1.30] and 1 patient received 3.7 GBq). Preparation according to each centre's policy: thyrotropin alfa (rhTSH) injected into the buttock muscle on each of the 2 days before ablation (the method recommended by the protocol; 82% of patients) or thyroid hormone withdrawal (18%): levothyroxine was stopped 4 weeks and triiodothyronine 2 weeks before ablation and restarted 2 days afterwards. The rhTSH dose and the low-iodine diet are not stated in the paper. 22 (9%) of the 253 patients in this group declined iodine after randomisation. Follow-up as in the no-iodine group.
No iodine ablation (251 patients; 2 later received ablation). Follow-up in both groups: neck ultrasound and stimulated thyroglobulin (with rhTSH or hormone withdrawal) at least 8 weeks after surgery (in the ablation group, before iodine); examination and thyroid tests (thyroglobulin and anti-thyroglobulin antibodies) 2 months later; stimulated thyroglobulin and ultrasound again 6 to 9 months after the first measurement; then examination and thyroid tests every 6 months and neck ultrasound every 12 months.
Source of the regimen details: Full text of the Lancet paper (Newcastle University repository version, Procedures section and treatment received) and ClinicalTrials.gov NCT01398085; the rhTSH dose and the low-iodine diet are not stated in the paper
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 years and older with WHO performance status 0 to 2 and low-risk differentiated thyroid cancer who had undergone total thyroidectomy (one- or two-stage) with complete tumour resection (R0) within the previous 6 months. Stage: pT1, pT2, pT3 (TNM7) or pT3a (TNM8) and N0, Nx or N1a; including papillary cancer without aggressive histological features (unifocal pT1a only with positive level VI nodes [pN1a]; multifocal pT1a; pT1b to pT3 confined to the thyroid; pT3 with minimal extrathyroidal extension as judged by the multidisciplinary team) and follicular cancer (including Hürthle cell/oncocytic) with minimal invasion and a size of 1 to 4 cm. Exclusion criteria: pN1b, M1, pT4, R1/R2 resection or lobectomy, aggressive subtypes (tall cell, columnar, diffuse sclerosing, poorly differentiated, anaplastic, widely invasive), follicular tumour larger than 4 cm, NIFTP, CT with IV contrast within 2 to 3 months before treatment, and previous treatment for thyroid cancer other than surgery (criteria from ClinicalTrials.gov). 77% of patients were women.
Endpoints
Primary endpoint: 5-year recurrence-free survival, defined as the absence of recurrent or persistent structural locoregional disease, distant metastasis or death from thyroid cancer. Analyses were done per protocol and by intention to treat (ITT); safety was analysed in the per-protocol population.
Safety and side effects
Adverse events were similar between the two groups; the most common were fatigue (25% in the no-ablation group versus 28% in the ablation group), lethargy (14% versus 14%) and dry mouth (10% versus 9%). Taste disturbance (grade 1 to 2) occurred in 1% versus 4% and sialadenitis in none versus 1%. Grade 3 events occurred in a total of 4 patients (2%) versus 1 patient (less than 1%). There were no treatment-related deaths.
Clinical significance and place in guidelines
IoN, together with ESTIMABL2, is the second large randomised trial to show the safety of omitting radioactive iodine in low-risk differentiated thyroid cancer, and unlike ESTIMABL2 its primary endpoint was structural recurrence with more than 5 years of follow-up. The 2025 American Thyroid Association (ATA) guideline does not recommend routine remnant ablation after total thyroidectomy in low-risk patients (strong recommendation, high-certainty evidence); IoN was published after the literature search for that guideline closed (July 2024) and reinforces this approach.
Limitations
The number of recurrence events was small (17 recurrences) and the non-inferiority margin of 5 percentage points is relatively wide. The number of patients with pT3/pT3a or N1a tumours was limited and the recurrence rate in these subgroups was higher; for this reason the authors restricted their conclusion to pT1, pT2 and N0/Nx tumours without adverse features. Follow-up is ongoing.
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.