In a prospective, randomised phase III study that involved patients with low-risk differentiated thyroid cancer, follow-up without the use of radioiodine after thyroidectomy was not inferior to the administration of 1.1 GBq of radioiodine after the administration of recombinant human thyrotropin. The findings from the ESTIMABL2 study are published by Dr. Sophie Leboulleux of the Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy, Université Paris Saclay in Villejuif, France and colleagues in the 10th March 2022 issue of The New England Journal of Medicine.
The majority of patients with thyroid cancer are at low risk for recurrence, and their risk of cancer-related death is even lower. After thyroidectomy, radioiodine (iodine-131) is generally administered both to ablate residual normal thyroid tissue and to treat persistent disease. Two large, randomised studies have shown that in patients with low-risk thyroid cancer, the postoperative administration of low-activity radioiodine (1.1 GBq) after injections of recombinant human thyrotropin was not inferior to the administration of high-activity radioiodine (3.7 GBq) after withdrawal of thyroid hormone treatment with respect to the ablation success rate at 1 year and the recurrence rate at 5 years.
The authors wrote in the background that there is a consensus to avoid radioiodine administration in patients with unifocal microcarcinoma, but the benefits of radioiodine administration in other patients with low-risk thyroid cancer remain controversial. The absence of prospective studies that address this question has been used as an argument in favour of recommending the use of radioiodine in all patients with low-risk thyroid cancer.
French researchers conducted the randomised, phase III ESTIMABL2 study involving patients with low-risk thyroid cancer to assess the non-inferiority of a follow-up strategy that does not include the postoperative administration of radioiodine as compared with radioiodine administration with respect to the percentage of patients without an event during 3 years after randomisation. They assigned patients with low-risk differentiated thyroid cancer who were undergoing thyroidectomy to receive ablation with postoperative administration of radioiodine (1.1 GBq) after injections of recombinant human thyrotropin (radioiodine group) or to receive no postoperative radioiodine (no-radioiodine group).
The primary objective was to assess whether no radioiodine therapy was not inferior to radioiodine therapy with respect to the absence of a composite endpoint that included functional, structural, and biologic abnormalities at 3 years. Non-inferiority was defined as a between-group difference of less than 5 percentage points in the percentage of patients who did not have events that included the presence of abnormal foci of radioiodine uptake on whole-body scanning that required subsequent treatment (in the radioiodine group only), abnormal findings on neck ultrasonography, or elevated levels of thyroglobulin or thyroglobulin antibodies. Secondary endpoints included prognostic factors for events and molecular characterisation.
Among 730 patients who could be evaluated 3 years after randomisation, the percentage of patients without an event was 95.6% (95% confidence interval [CI] 93.0 to 97.5) in the no-radioiodine group and 95.9% (95% CI 93.3 to 97.7) in the radioiodine group, a difference of −0.3 percentage points (two-sided 90% CI −2.7 to 2.2), a result that met the non-inferiority criteria.
Events consisted of structural or functional abnormalities in 8 patients and biologic abnormalities in 23 patients with 25 events. Events were more frequent in patients with a postoperative serum thyroglobulin level of more than 1 ng per milliliter during thyroid hormone treatment.
A subgroup of tumours underwent mutational analysis, with the BRAF V600E mutation found in approximately half the samples in each group. Although tumours with this mutation often behave more aggressively, event rates did not differ between groups according to mutational status in these low-risk patients.
There were no differences in quality-of-life scores between the two groups. No treatment-related adverse events were reported.
The study team observed that less than 5% of the patients in the two groups had events that included abnormal findings on whole-body scanning or neck ultrasonography or elevated levels of thyroglobulin or thyroglobulin antibodies during the first 3 years of follow-up. This rate is concordant with the definition of low-risk thyroid cancer, and the study showed that the risk of events was not higher in the absence of postoperative administration of radioiodine. The patients in the study were representative of patients with a pT1 thyroid tumour measuring 20 mm or less, a category that constitutes 50% to 70% of all thyroid cancers and 65% to 75% of those with a nodal status of N0 or Nx.
The authors commented that their results should be confirmed with longer follow-up. However, in previous retrospective studies involving patients with low-risk thyroid cancer, most recurrences occurred during the first 5 years of follow-up. The 3-year period in this study allowed for control of indeterminate findings over time while limiting loss to follow-up.
In an accompanied editorial, Dr. David S. Cooper of the Johns Hopkins University School of Medicine in Baltimore, MD, US commented that during the past decade, the use of radioiodine has decreased, at least among younger patients with differentiated thyroid cancer. Although radioiodine therapy for differentiated thyroid cancer was introduced in the 1940s and 1950s, there would be finally evidence to enable clinicians to maximise its benefits and minimise its risks.
The study was supported by the French Ministry of Health through a grant from the French National Cancer Institute.