Thyroidectomy with or without postoperative radioiodine for patients with low-risk differentiated thyroid cancer in the UK (IoN): a randomised, multicentre, non-inferiority trial

Background Patients with differentiated thyroid cancer can often be treated with postoperative radioiodine (also called radioiodine ablation) after total thyroidectomy. The IoN trial was designed to assess whether recurrence-free survival was non-inferior after no ablation compared with ablation in patients with low-risk differentiated thyroid cancer. Methods IoN was a multicentre, non-inferiority, phase 3 randomised trial conducted at 33 UK cancer centres. Eligible patients had complete (R0) resection following total thyroidectomy; stage pT1, pT2, pT3 (according to Tumour, Node, Metastasis staging version 7 [TNM7]), or pT3a (according to TNM8) disease; and N0, Nx, or N1a disease. Participants were randomly assigned (1:1) by minimisation, using a central electronic system, to have either 1<middle dot>1 GBq ablation or no ablation, following thyroidectomy. Stratification factors were centre, age, T stage, and nodal status. Patients had annual neck ultrasound scans and 6-monthly serum thyroglobulin measurements. The primary endpoint was 5-year recurrence-free survival, defined by the absence of locoregional recurrent or persistent structural disease, distant metastases, or death from thyroid cancer. Non-inferiority was assessed with a margin of 5 percentage points. Per-protocol and intention-to-treat (ITT) analyses were done for the primary endpoint, and safety was analysed in the per-protocol population. The trial is registered with ClinicalTrials.gov (NCT01398085), ISRCTN (ISRCTN80416929), and EUDRACT (2011-000144-21), and is still in active follow-up. Findings We recruited 504 patients (including 390 [77%] female patients and 114 [23%] male patients) between June 26, 2012 and March 18, 2020 and randomly assigned 251 to receive no ablation and 253 to receive ablation (ITT population). 249 patients in the no ablation group did not have ablation and 231 in the ablation group had ablation (per-protocol population). Median follow-up was 6<middle dot>8 years (IQR 5<middle dot>6-8<middle dot>6) in the no ablation group and 6<middle dot>6 years (4<middle dot>8-8<middle dot>5) in the ablation group; 17 recurrences (eight in the no ablation group and nine in the ablation group; ITT population) occurred during follow-up. 5-year recurrence-free rates were 97<middle dot>9% (95% CI 96<middle dot>1-99<middle dot>7) in the no ablation group versus 96<middle dot>3% (93<middle dot>9-98<middle dot>7) in the ablation group in the ITT analysis, and 97<middle dot>9% (96<middle dot>1-99<middle dot>7) versus 96<middle dot>9% (94<middle dot>7-99<middle dot>1) in the per-protocol analysis. The 5-year absolute risk difference was 0<middle dot>5 percentage points (95% CI-2<middle dot>2 to 3<middle dot>2, pnon-inferiority=0<middle dot>033; ITT analysis), showing that non-inferiority was reached. The observed recurrence rate was higher among patients with pT3 or pT3a tumours (four [9%] of 46 patients overall with pT3 or pT3a tumours vs 13 [3%] of 458 with pT1 or pT2 tumours), or N1a tumours (six [13%] of 47 with N1a vs 11 [2%] of 457 with N0 or Nx), but they were similar among those who did not receive ablation. Adverse events were similar between the groups, the most common being fatigue (63 [25%] of 249 in the no ablation group vs 65 [28%] of 231 in the ablation group), lethargy (34 [14%] vs 32 [14%]), and dry mouth (24 [10%] vs 21 [9%]), and there were no treatment-related deaths. Interpretation The IoN trial shows that ablation (or postoperative radioiodine) can be avoided for patients with pT1, pT2, and N0 or Nx tumours with no adverse features. Many patients with low-risk differentiated thyroid cancer worldwide can safely avoid postoperative radioiodine and its related hospitalisation and side-effects, which in turn results in lower health-care costs.