Highlights
- The IoN trial found that omitting postoperative radioiodine ablation after total thyroidectomy in low-risk differentiated thyroid cancer does not compromise 5-year recurrence-free survival.
- Recurrence rates were low and similar between ablation and no-ablation groups, with no significant difference in adverse events.
- Findings support the safe avoidance of radioiodine in patients with pT1, pT2, and N0/Nx disease, potentially reducing healthcare costs and side effects.
Study Background and Disease Burden
Differentiated thyroid cancer (DTC) is the most common endocrine malignancy, with a rising incidence globally but relatively low disease-specific mortality, especially in low-risk cases. Standard management for low-risk DTC typically involves total thyroidectomy followed by selective use of postoperative radioactive iodine (RAI) ablation to eradicate residual thyroid tissue and enable disease monitoring via thyroglobulin levels. However, the necessity of RAI in low-risk patients has been increasingly questioned, given its potential for adverse effects (such as salivary gland dysfunction, secondary malignancies, and hospitalisation) and lack of clear mortality benefit in this population. The IoN trial was designed to address the critical clinical question of whether RAI ablation is essential for recurrence prevention in low-risk DTC patients.
Study Design
The IoN study was a multicentre, phase 3, non-inferiority randomised controlled trial conducted at 33 UK cancer centres. The trial included patients with histologically confirmed, low-risk DTC who had undergone complete (R0) resection via total thyroidectomy. Eligible patients had tumours staged as pT1, pT2, or pT3 (TNM7), or pT3a (TNM8), with nodal status N0, Nx, or N1a, and no adverse features.
Patients were randomised 1:1 to receive either no RAI ablation or a single 1.1 GBq dose of RAI ablation. Randomisation was stratified by centre, age, T stage, and nodal status to ensure balanced allocation. Follow-up included annual neck ultrasound and 6-monthly serum thyroglobulin (Tg) assessments for at least 5 years. The primary endpoint was 5-year recurrence-free survival (RFS), defined as the absence of locoregional or distant recurrence, persistent structural disease, or thyroid cancer-specific death. Both intention-to-treat (ITT) and per-protocol analyses were performed, with a non-inferiority margin set at 5 percentage points.
Key Findings
A total of 504 patients were enrolled, with 251 assigned to no ablation and 253 to ablation. The median follow-up exceeded 6 years in both groups. Key results included:
– The 5-year RFS was 97.9% (95% CI 96.1–99.7) in the no ablation group and 96.3% (93.9–98.7) in the ablation group (ITT analysis).
– The absolute risk difference was 0.5 percentage points (95% CI −2.2 to 3.2; p for non-inferiority = 0.033), confirming non-inferiority.
– Per-protocol analysis yielded similar findings: 5-year RFS of 97.9% (no ablation) versus 96.9% (ablation).
– There were 17 recurrences in total: 8 in the no ablation group and 9 in the ablation group.
– Recurrence was more frequent among patients with pT3/pT3a (9% recurrence) or N1a (13%) disease compared to those with pT1/pT2 (3%) or N0/Nx (2%), but the benefit of ablation did not differ significantly within these subgroups.
– Adverse event profiles were similar: fatigue (25–28%), lethargy (14%), and dry mouth (9–10%) were most common. No treatment-related deaths occurred.
These data robustly support the omission of postoperative RAI in the majority of low-risk DTC patients who have undergone complete surgical resection and have no adverse high-risk features.
Expert Commentary
The IoN trial provides some of the most definitive evidence to date addressing the longstanding debate regarding RAI use in low-risk DTC. Its pragmatic, real-world approach—broad eligibility criteria, multicentre setting, and rigorous follow-up—enhances the generalisability of findings. These results are in line with evolving guidelines from the American Thyroid Association and European Thyroid Association, which have been moving toward more selective RAI use, particularly in low-risk populations.
Importantly, the IoN trial confirms that most recurrences in this population are rare, indolent, and not reduced by routine RAI ablation. The comparable safety profile and the absence of treatment-related mortality further strengthen the case for de-escalation. However, the trial does highlight that patients with pT3/pT3a or N1a disease, while still considered low risk, demonstrate higher recurrence rates; the benefit of RAI in these subgroups remains less clear and may warrant further stratified investigation.
Limitations include the relatively small number of recurrences (reflecting the low event rate in this population), which restricts the statistical power for subgroup analyses. Additionally, while follow-up was sufficient for the primary endpoint, late recurrences beyond 5–7 years remain possible. Nonetheless, the trial’s rigorous design and comprehensive follow-up make its conclusions highly reliable for clinical practice.
Conclusion
The IoN trial provides high-level evidence that postoperative RAI ablation can be safely omitted in the majority of patients with low-risk differentiated thyroid cancer following total thyroidectomy, without compromising recurrence-free survival or increasing adverse events. This finding supports a shift towards more individualised, risk-adapted treatment algorithms, reducing unnecessary exposure to radioiodine, minimising side effects and costs, and enhancing patient quality of life. Further research may elucidate whether certain so-called low-risk subgroups (notably pT3/pT3a or N1a) might benefit from more tailored risk assessment and follow-up strategies.
References
Mallick U, Newbold K, Beasley M, Garcez K, Wadsley J, Johnson SJ, Stephenson T, Gaze M, Goodman A, Jefferies S, Sivabalasingham S, Slevin N, Wilkinson DP, Macias-Fernandez E, Power D, Roques T, Speed L, Nutting C, Mochloulis G, Gerrard G, Candish C, Morgan S, Tripathi D, Truran P, Arthur C, Wieczorek A, Madhavan K, Maclean J, Boote D, Kim D, Pascoe A, Pitiyage G, Forsyth S, Ambrose E, Chang E, Farnell K, Hackshaw A. Thyroidectomy with or without postoperative radioiodine for patients with low-risk differentiated thyroid cancer in the UK (IoN): a randomised, multicentre, non-inferiority trial. Lancet. 2025 Jul 5;406(10498):52-62. doi: 10.1016/S0140-6736(25)00629-4. Epub 2025 Jun 18. PMID: 40543520.
American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016 Jan;26(1):1-133. doi: 10.1089/thy.2015.0020.