Robert Flavell, MD, PhD, University of California San Francisco, discusses the 2025 update to the American Thyroid Association (ATA) Guidelines for the Treatment of Differentiated Thyroid Cancer. In this video, he highlights key changes for oncologists regarding radioactive iodine (RAI) use, risk stratification, and management of radioiodine-refractory disease. 

The updated guidelines introduce a revised 4-tier risk stratification system, providing clearer recommendations on when to use RAI and place greater emphasis on pre- and post-therapy imaging with SPECT/CT. The guidelines also recommend molecular testing in RAI-refractory cases and consider redifferentiation therapy in selected patients with actionable mutations, reflecting a more evidence-based and interdisciplinary approach to thyroid cancer management.

Access the guidelines.

Transcript:

 Hi, I'm Rob Flavell. I'm a physician scientist and Chief of the Division of Molecular Imaging and Therapeutics at University of California in San Francisco. I'm a practicing nuclear medicine physician and radiologist with interest in thyroid cancer treatment. 

I'm going to give a recap on a recent presentation I gave at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) Theranostics Conference on the topic of thyroid cancer guidelines, with a particular focus on the American Thyroid Association (ATA) Guidelines for the treatment of differentiated thyroid cancer, which is a publication that's issued periodically. The most recent version was published in 2025. I was one of the authors on this from the nuclear medicine perspective. And this is widely used guidelines in the field for nuclear medicine treatment for thyroid cancer. 

By way of background, radioactive iodine is a widely used treatment for thyroid cancer. It's been around for a long time, actually. It was used now for over 80 years, and there is a reason why it's been used for so long, because it's an effective treatment for patients with thyroid cancer. It's used routinely for patients for remnant ablation, adjuvant therapy, and treatment of metastatic disease. 

Now, although it's been around for a long time and in its effective therapy, there's a lot of things that are somewhat challenging about studying radioactive iodine compared to the other types of radiopharmaceutical therapies that are now garnering a lot of attention. These other therapies such as lutetium PSMA, lutetium-dotatate, radium-223, etc. These have been approved over the last 10 to 15 years and have now emerged as part of the mainstream. 

These are administered in a very different way compared to radioactive iodine. They're given typically as fixed activity regimens. In clinical trials, these are relatively easy to study because they have relatively high event rates, meaning they're typically administered late in the course of the disease, so the patients tend to progress relatively quickly. And the use of these drugs is supported by a strong evidence base from prospective randomized phase 3 trials, which are conducted using recent methodologies. 

In contrast, Iodine 131 is very different. It has a highly variable dosing. It's based on the prescribing nuclear medicine physician's practice. It's typically administered as a single dose as compared to the other therapies which are done as multiple doses. It is typically administered early in the disease course as the first step after total thyroidectomy, and it's supported by a heterogeneous, largely retrospective and observational evidence base accumulated over many years. 

Now, by way of background, the last version of the ATA guidelines were produced in 2015 before this more recent 2025 update. The ATA is an interdisciplinary society of clinicians and researchers focused on thyroid disease. The 2015 guidelines were regarded as controversial by the nuclear medicine community in some areas, particularly radiodine-refractory disease were considered controversial. This led to a subsequent dialogue between these various societies, the ATA, SNMMI, European Thyroid Association, and the European Society of Nuclear Medicine, and subsequent associated publications. 

Now, despite this, there remains considerable heterogeneity in the practice of treatment with radioactive iodine for thyroid cancer. These guidelines will now include particular areas where there's strong evidence for support, where there's high grade evidence, but recognizing that in real life, that there's a lot of areas where we don't have all the information, but still to provide some helpful information to clinicians. 

So what was new in the 2025 guidelines of the ATA? So this first of all separated out thyroid nodules for differentiated thyroid cancer management, and there was a greater emphasis on evidence-based recommendations and assessment of data strength. And this does lead to a lot of recommendations that are conditional because as I mentioned, a lot of the data supporting the use of radioactive iodine is retrospective and observational. And it incorporated a lot of these principles from these interdisciplinary meetings that occurred after the 2015 ATA guidelines. 

A major change was splitting the risk of structural recurrence up into 4 categories instead of 3 categories. Previously, this was 3 categories: low, intermediate, and high. The intermediate category was now broken down into 2 groups: low-intermediate and intermediate-high. I'm going to just flash the new framework up on the screen here for a sec so you can all see it. I do recommend that you read the new guidelines for your own interest. 

It really essentially has broken this down into 4 categories now and I think cleaned it up quite a bit. It separated out the papillary group in this left column here, the follicular thyroid cancer in the middle group, and the oncocytic thyroid cancer, or hertho-cell carcinoma, in the left group. And I think it really kind of cleaned up and made it simpler to determine risk stratification in the individual patient. There's less ambiguity in the new table. I’m not going to have time to go over this all in great detail, but I encourage you to use this in your own thyroid cancer treatment practice. 

Some other areas where there were significant changes was in the recommendations for thyroid cancer treatment with radioactive iodine. In the high-risk group, there was retained a strong recommendation for treatment with radioactive iodine routinely because these patients have a high risk of recurrence. In the low-risk group, the recommendation was to not routinely perform remnant ablation for patients with low-risk differentiated thyroid cancer. And this was supported by some of the more recent data from the ESTIMABLE-2 trial, which supported equivalent of observation vs radioactive iodine in patients with ATA low-risk thyroid cancer. The intermediate risk group remains an overall support for considering radioactive iodine therapy in this patient population, although this certainly leaves room for the individual clinician to make their own judgment about if radioactive iodine is appropriate for their patient. 

One other change on this new version of the ATA guideline was a greater support and emphasis on obtaining both pre-treatment and post-treatment radioactive iodine imaging and to include it routinely with SPECT/CT. In this day and age, SPECT/CT is routinely available in most nuclear medicine departments, and it should be used for thyroid cancer. It does help considerably in distinguishing areas of benign or physiologic uptake on a post-therapy scan or a pre-therapy scan versus things that are malignant. So greater emphasis this time around on pre-therapy and post-therapy scanning using SPECT/CT. 

And some other areas where there was some new recommendations was in the areas of redifferentiation therapy. This refers to the administration of a kinase inhibitor to redifferentiate thyroid cancer to produce genes that make them sensitive to treatment with radioactive iodine. It was recommended that patients who have radioactive iodine-refractory thyroid cancer mean they've progressed after the treatment. 

Previously with radioactive iodine, they should undergo tissue-based biomarker testing, probably with a biopsy and genetic testing. And then when appropriate those patients who undergo this testing and have an actionable mutation, that redifferentiation by MAP kinase pathway blockade in patients with this progressive radioiodine-refractory differentiated thyroid cancer could be considered in selected patients. And there's a particular interest here to get patients onto clinical trials because most of the data here is from small clinical trials. 

It is not recommended to perform redifferentiation approaches in patients who do not have a molecularly actionable therapy.

In summary, the new version of the ATA Differentiated Thyroid Cancer Guidelines include several recommendations that are highly relevant to nuclear medicine physicians and patients with thyroid cancer who are considering treatment with radioactive iodine. And I've summarized some of the major changes here. I highly encourage you to review the actual document. It's pretty extensive. It's really more of a reference, but certainly to review the sections that are relevant to your own clinical practice. 

Thanks very much for your attention.