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THYROID CANCER
2025 ATA Differentiated Thyroid Cancer Guidelines: Systemic Therapy

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BACKGROUND
The majority of patients with thyroid cancer do very well with an excellent prognosis. This is because we have very effective treatments, including surgery to remove the cancer and radioactive iodine therapy to destroy any remaining thyroid cancer after surgery. However, 5 to 15% of patients have more advanced cancer which can develop resistance to radioactive iodine therapy, which is linked to markedly worse clinical outcomes. Systemic therapy (ie chemotherapy) is reserved for patients with progressive, symptomatic cancer that fails to respond to radioactive iodine therapy and cannot be surgically removed. Systemic therapy is typically started when cancer growth exceeds 20% over 12 to 14 months.

The 2025 ATA thyroid cancer guidelines provide the first comprehensive framework directly linking molecular gene mutations in the cancer to available options for treatment.

THE FULL ARTICLE TITLE
 Ringel MD et al. 2025 American Thyroid Association management guidelines for adult patients with differentiated thyroid cancer. Thyroid 2025;35(8):841-985.

SUMMARY OF THE STUDY
The 2025 ATA thyroid cancer guidelines refer to patients with differentiated thyroid cancer, almost all of which are papillary thyroid carcinoma. A major change is that comprehensive molecular testing of the cancer is now mandated prior to selecting first-line systemic therapy in patients with persistent thyroid cancer that no longer responds to radioactive iodine therapy.

If the patient’s cancer does not have any cancer mutation that can be targeted with specific systemic therapy, the majority of patients will receive multi-kinase inhibitor drugs as first-line treatment. Lenvatinib is generally preferred over sorafenib. However, for the subset of patients whose cancers that have mutations that can be targeted by specific chemotherapy drugs, selective inhibitors are now preferred for first-line therapy—a significant shift in recommendations. In addition, combination therapy can be selected based on specific cancer gene mutations.

The guidelines also emphasize the importance of dose decreases and early management of common toxic side effects, including high blood pressure, kidney disease and fatigue, are critical to continuing treatment and maximizing clinical benefits.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
Molecular testing of thyroid cancer now defines first-line systemic therapy in progressive thyroid cancer that no longer responds to radioactive iodine therapy and cannot be removed by surgery. The 2025 ATA thyroid cancer management guidelines redefine the management of advanced DTC, shifting the question from “Which drug?” to “What gene mutation is driving the cancer?” As always, these decisions should result from a shared-decision making discussion with the patient and their doctor.

— Alan P. Farwell, MD

ABBREVIATIONS & DEFINITIONS

Papillary thyroid cancer: the most common type of differentiated thyroid cancer. There are 4 variants of papillary thyroid cancer: classic, follicular, tall-cell and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

Follicular thyroid cancer: the second most common type of differentiated thyroid cancer.

Thyroidectomy: surgery to remove the entire thyroid gland. When the entire thyroid is removed it is termed a total thyroidectomy. When less is removed, such as in removal of a lobe, it is termed a partial thyroidectomy.

Radioactive iodine (RAI): this plays a valuable role in diagnosing and treating thyroid problems since it is taken up only by the thyroid gland. I-131 is the destructive form used to destroy thyroid tissue in the treatment of thyroid cancer and with an overactive thyroid. I-123 is the nondestructive form that does not damage the thyroid and is used in scans to take pictures of the thyroid (Thyroid Scan) or to take pictures of the whole body to look for thyroid cancer (Whole Body Scan).

Mutation: A permanent change in one of the genes.

Genes: a molecular unit of heredity of a living organism. Living beings depend on genes, as they code for all proteins and RNA chains that have functions in a cell. Genes hold the information to build and maintain an organism’s cells and pass genetic traits to offspring.

Cancer-associated genes: these are genes that are normally expressed in cells. Cancer cells frequently have mutations in these genes. It is unclear whether mutations in these genes cause the cancer or are just associated with the cancer cells. The cancer-associated genes important in thyroid cancer are BRAF, RET/PTC, TERT and RAS.

microRNA: a short RNA molecule that has specific actions within a cell to affect the expression of certain genes.

Tyrosine kinases: proteins that are overactive in many of the pathways that cause cells to be cancerous.

Tyrosine kinase inhibitors: Chemotherapy drugs that are used to treat thyroid cancer that no longer responds to radioactive iodine and cannot be removed by surgery. These drugs can target a single tyrosine kinase or multiple tyrosine kinases. Examples of these drugs are Levatinib and Sorafinib.

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