A landmark UK phase III trial has demonstrated that patients with low-risk differentiated thyroid cancer can safely forgo postoperative radioiodine ablation following thyroidectomy without compromising long-term survival outcomes. The IoN trial, published in The Lancet, provides compelling evidence that could reshape treatment protocols for thousands of thyroid cancer patients globally.
Trial Design and Patient Population
The multicenter noninferiority trial enrolled 504 patients across 33 UK cancer centers between June 2012 and March 2020. Patients underwent complete (R0) resection via total thyroidectomy and had stage pT1, pT2, pT3 (TNM version 7) or pT3a (TNM version 8) disease with N0, Nx, or N1a nodal status. Participants were randomly assigned to receive either no ablation (n=251) or radioiodine ablation with 1.1 GBq (n=253).
The patient population was well-balanced between treatment arms, with a median age of approximately 48 years and 78% female representation. Papillary carcinoma was the predominant histologic subtype (76% in no-ablation group vs 81% in ablation group), followed by follicular carcinoma (21% vs 15%). Multifocal tumors were present in 35% of no-ablation patients and 38% of ablation patients.
Primary Efficacy Outcomes
At a median follow-up of 6.8 years in the no-ablation group and 6.6 years in the ablation group, the trial met its primary endpoint of demonstrating noninferiority. Five-year recurrence-free survival rates were 97.9% (95% CI: 96.1%-99.7%) in the no-ablation group versus 96.3% (95% CI: 93.9%-98.7%) in the ablation group in the intention-to-treat population.
The 5-year absolute risk difference was 0.5 percentage points (95% CI: -2.2 to 3.2 percentage points), well within the prespecified noninferiority margin of 5 percentage points. The P value for noninferiority of .033 was statistically significant, confirming that omitting radioiodine ablation did not compromise patient outcomes.
Overall, there were 8 recurrences in the no-ablation group compared with 9 in the ablation group across the study period.
Risk Stratification Insights
The trial revealed important patterns in recurrence risk based on tumor and nodal characteristics. Recurrence rates were notably higher among patients with pT3 or pT3a tumors compared to pT1 or pT2 tumors (9% vs 3%, respectively). Similarly, patients with N1a nodal status experienced higher recurrence rates than those with N0 or Nx status (13% vs 2%).
Importantly, these risk patterns were consistent regardless of whether patients received ablation, suggesting that tumor biology rather than treatment approach drives recurrence risk in these subgroups.
Safety Profile
Adverse events occurred at comparable rates between treatment groups in the per-protocol population. The most frequently reported adverse events were fatigue (25% in no-ablation arm vs 28% in ablation arm), lethargy (14% in both groups), and dry mouth (10% vs 9%). Grade 3 adverse events occurred in four patients (2%) in the no-ablation group and one patient (<1%) in the ablation group. No grade 4 adverse events or treatment-related deaths were observed.
Clinical Implications
The investigators concluded that "ablation (or postoperative radioiodine) can be avoided for patients with pT1, pT2, and N0 or Nx tumors with no adverse features." This finding has significant implications for clinical practice, as it could eliminate the need for radioiodine treatment in many thyroid cancer patients worldwide.
The study authors emphasized that avoiding postoperative radioiodine would result in "lower health-care costs" while eliminating the need for hospitalization and associated side effects. This represents a paradigm shift toward de-escalated treatment approaches in low-risk thyroid cancer management.
Lead investigator Ujjal Mallick from the Department of Oncology at Freeman Hospital in Newcastle, UK, noted that "long-term follow-up of the IoN trial shows that ablation is unnecessary in patients with differentiated thyroid cancer, specifically those with pT1 or T2 tumors that are N0 or Nx."
The trial's findings support a more personalized approach to thyroid cancer treatment, where patients with favorable tumor characteristics can avoid unnecessary interventions while maintaining excellent long-term outcomes.
