BACKGROUND
Thyroid cancer is common and usually has an excellent prognosis. This is because we have very effective therapies, beginning with surgery. Radioactive iodine therapy is one of the treatment options available for the management of thyroid cancer following total thyroidectomy. Radioactive iodine works as a “magic bullet” as it is taken up and stored only by thyroid cells, both normal and cancerous, and destroys them. While in the past most patients were treated with radioactive iodine therapy, the more recent practice is to be selective when considering who would benefit from this treatment. This allows avoiding unnecessary exposure of patients to the side effects of radioactive iodine therapy, including radiation exposure and damage to the salivary glands leading to dry mouth. Prior studies have demonstrated that patients with thyroid cancer with a low risk of recurrence do not require routine treatment with radioactive iodine therapy. It is unclear, however, if patients with a slightly higher risk of recurrence (intermediate risk) should be routinely offered radioactive iodine therapy.

The IoN trial was designed to assess whether observation (i.e., not administering radioactive iodine therapy) provided similar outcomes compared to administering radioactive iodine therapy in patients with thyroid cancer with a low-to-intermediate risk of recurrence.

THE FULL ARTICLE TITLE
Mallick U, et al. 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;406(10498):52-62.doi: 10.1016/S0140- 6736(25)00629-4. PMID: 40543520.

SUMMARY OF THE STUDY
The study was performed in 33 centers in the United Kingdom. Patients who had a diagnosis of papillary thyroid cancer (any size) or patients with minimally invasive follicular thyroid cancer (up to 4 cm) without extensive vascular invasion were recruited to participate.

Patients had either no evidence of cancer spreading to the lymph nodes in the neck or spread limited to the lymph nodes in the central part of the neck around the thyroid gland. Patients were not included in the study if there was significant extrathyroidal extension (extension of the cancer beyond the margins of the thyroid gland), aggressive features on pathology, if surgery could not removal all visible cancer in the neck or if there was evidence of distant metastasis (spread of cancer to other parts of the body beyond the neck). Patients were randomly assigned to be treated with radioactive iodine therapy (“ablation group”, most receiving ~30 mCi of I-131) or not be treated (“no ablation group”) and were monitored with periodic blood tests (TSH, thyroglobulin) and neck ultrasound imaging.

A total of 251 patients were included in the no-ablation group (out of which 2 patients ended up getting radioactive iodine therapy) and 253 patients in the ablation group (out of which 22 patients decided not to have ablation) with an average follow up period of 6.7 years. There were no cancer-related deaths in either group. The 5-year recurrence free survival rates (no evidence of cancer coming back) were similar in both groups, 97.9% in the no ablation group versus 96.3% in the ablation group. Overall 8 patients had recurrences in the no ablation group and 9 in the ablation group.

In the total study population, having thyroglobulin levels above a threshold after surgery, cancers greater than 4 cm or the presence of metastatic nodes in the center of the neck were associated with a higher risk for recurrence. However, the study was not large enough to determine whether radioactive iodine therapy would be beneficial over no treatment in these sub-groups.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
In select patients with thyroid cancer with low-to-intermediate risk of recurrence, radioactive iodine therapy does not provide additional benefit over not treating. This study suggests that in patients with cancer that are less than 4 cm without any other high-risk features, radioactive iodine therapy does not have to be part of the routine therapy.

However, further research is required to assess certain lowintermediate risk subgroups such as cancers that are larger than 4 cm and when metastatic central neck nodes are present. In addition, factors that were not evaluated in the study, such as the molecular profile of the cancer, will need to be investigated further.

— Poorani Goundan, MD

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