Radioactive Iodine Shows No Benefit in Low-Risk Thyroid Cancer

Nancy A. Melville

March 09, 2022

Patients with low-risk differentiated thyroid cancer (DTC) undergoing thyroidectomy show no improvements in outcomes with the use of postoperative radioiodine ablation compared to those who do not receive this therapy, suggesting these patients can be spared the previously common treatment.

The study's take-home message for clinicians should be to "stop systematic radioiodine ablation administration in low-risk thyroid cancer patients," lead author Sophie Leboulleux, MD, PhD, told Medscape Medical News.

The results were first reported at ENDO 2021 and have now been published in the New England Journal of Medicine by Leboulleux, of the Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy Cancer Institute, Villejuif, France, and colleagues.

While American Thyroid Association (ATA) guidelines already indicate that radioiodine ablation is not routinely recommended after thyroidectomy for patients with low-risk thyroid cancer, the guidance is only a "weak recommendation," supported by "low-quality evidence."  

Dr David S. Cooper

However, the new findings should give that level of evidence a much-needed boost, said one expert. "I think the main contribution of this paper is to change the evidence level to 'high quality,' therefore making the recommendation 'strong,' rather than 'weak'," David S. Cooper, MD, told Medscape Medical News.

Cooper, a professor of medicine and radiology at the Johns Hopkins University School of Medicine, in Baltimore, Maryland, also wrote an editorial that accompanies Leboulleux's study.

The ability to safely spare patients the radioiodine ablation step after thyroidectomy also has important benefits in terms of cost and convenience, Cooper stressed.


The new findings are from the prospective, randomized, phase 3 Essai Stimulation Ablation 2 (ESTIMABL2) trial, in which 730 patients at 35 centers in France with low-risk DTC scheduled to undergo thyroidectomy were enrolled between May 2013 and March 2017.

Patients were randomized to receive either postoperative radioiodine ablation (1.1 GBq) after injections of recombinant human thyrotropin (n = 363) or no postoperative radioiodine (n = 367).

Patients were a mean age of 52 years and 83% were women. About 96% had papillary tumors, and pathological tumor node (pTN) stages were mostly pT1b thyroid with a nodal status of N0 or Nx (81.1%). It is these patients in particular in whom retrospective studies of the use of radioiodine ablation have yielded inconsistent results, Leboulleux and colleagues note. Hence, their decision to look at this prospectively.

Outcomes were based on the groups' rates of events, defined as the presence of abnormal foci of radioiodine uptake on whole-body scanning that required treatment (in the radioiodine group only), abnormal findings on neck ultrasonography, or increased levels of thyroglobulin or thyroglobulin antibodies.

After a 3-year follow-up, the rates of having no events in both groups were very high — and nearly identical — at 95.6% among those receiving no radioiodine ablation and 95.9% in the radioiodine group, for a between-group difference of –0.3 percentage points, which met the criteria for noninferiority for the no-radioiodine group.

Likewise, the events that did occur were also nearly equally split between the no-radioiodine group (16 events, 4.4%) and the radioiodine group (15 events, 4.1%).

Among patients who had events, subsequent treatments, including surgery, radioiodine administration, or both, were necessary for four patients in the no-radioiodine group and 10 in the radioiodine group, and additional treatments were not necessary for the other patients who experienced events.

There were no differences between those who did and did not experience events in terms of molecular alterations, and 50 of the tumors had BRAF mutations, with no significant differences between groups.

Of the adverse events that occurred in 30 patients, none were determined to be related to treatment, and there were no thyroid-related deaths.

The recurrence rates align with the rates observed overall with low-risk thyroid cancer, the authors note. 

"We 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," they report.

"This rate is concordant with the definition of low-risk thyroid cancer, and our trial showed that the risk of events was not higher in the absence of postoperative administration of radioiodine."

Patients Spared Costs, Work Losses

Cooper elaborated on the advantages, for patients, of avoiding radioiodine ablation.

For one thing, the recombinant human TSH that is necessary to prepare for radioiodine therapy is very expensive, ranging from $2000 to $3000, with patients often having a co-pay, he explained.

"Also, patients usually have to take time off work, which is also an expense to society and to them if they don't get paid for days that they don't work," Cooper added.

A possible study limitation is the question of whether 3 years is an ample follow-up period to detect events. However, Cooper said he considers the period to be sufficient.

"As the authors point out, most recurrences of thyroid cancer are detected within the first 3 to 5 years of initial treatment, so...the 3-year window is still clinically relevant," he said.

Regarding the study only including centers in France, Cooper added, "I do not think that this is a study limitation. There is nothing specific about the French population that would lead me to conclude that the results were not generalizable to all populations with low-risk papillary thyroid cancer."

Some Continue Radioiodine Use, But Lobectomies Add to Decline

Despite the mounting evidence of the lack of benefit of radioiodine ablation in low-risk patients, some centers, particularly in Europe, continue the practice, which was standard in the treatment of DTC until relatively recently.

"[While] US guidelines changed in 2015 in favor of no radioiodine in low-risk differentiated thyroid cancer patients, this study should help to change European guidelines," Leboulleux said. "The results will help to change practice both in the US and in Europe."

In addition to awareness of guidelines and new evidence, another reason for the decline in radioiodine ablation for low-risk DTC is the increasing use of thyroid lobectomy, which does not involve the use of radioiodine ablation, rather than total thyroidectomy, Cooper noted.

"The [new] NEJM paper will hopefully decrease the inappropriate use of radioiodine in low-risk patients even further," he concluded.

The study received support from the French Ministry of Health through a grant from the National Cancer Institute. The authors have reported no relevant financial relationships.

N Engl J Med. Published March 9, 2022. Abstract, Editorial

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