Differentiated thyroid cancer (DTC) is the most common cancer of the thyroid. Treatment usually includes surgery to remove part or all of the thyroid and radioactive iodine therapy. Radioactive iodine resistant (RAIR) DTC is more difficult to treat. Newer systemic therapies can slow disease progression and extend the lives of patients with this form of thyroid cancer.
In today's side-by-side comparison, we look at the latest clinical practice guidelines from the National Comprehensive Cancer Network (NCCN), the American Thyroid Association (ATA), and the American Society of Clinical Oncology (ASCO) on systemic therapies for RAIR DTC. These guidelines cover far more than systemic therapies for RAIR DTC, so we encourage you to review the full guidelines for more information.
| Item | Thyroid Carcinoma | 2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer | Systemic Treatment of Thyroid Cancer: ASCO Guideline |
|---|---|---|---|
| Authoring Organization | National Comprehensive Cancer Network | American Thyroid Association | American Society of Clinical Oncology |
| Publication Date | March 2025 | August 2025 | April 2026 |
| Graded Recommendations | Yes | Yes | Yes |
| Links | Full Text | Summary / Full Text | Summary / Full Text |
Key Takeaways
General
- The NCCN guideline is a living guideline updated frequently to keep up with medical advances. It includes recommendations for the management of all thyroid cancers, not just DTC.
- The ATA guideline provides 84 evidence-based recommendations for the diagnosis and treatment of DTC in adults.
- The ASCO guideline focuses only on systemic therapies that can be used to treat thyroid cancers. It includes 10 recommendations for systemic therapies for DTC.
Multi-Kinase Inhibitors
- Lenvatinib or sofafenib
- All three guidelines consider these to be first-line therapies with preference for lenvatinib.
- The ATA also made recommendations regarding lenvatinib dosing, Multi-kinase inhibitors (MKI) timing, and prevention and management of adverse events.
- Cabozantinib
- All three societies recommend cabozantinib as a subsequent-line therapy for patients who had progression or were not able to tolerate lenvatinib and/or sorafenib.
Immune checkpoint Inhibitors
- Pembrolizumab
- The NCCN and ASCO recommend considering adding pembrolizumab to lenvatinib for patients who have disease progression on lenvatinib alone.
- The NCCN and ATA both consider offering an immune checkpoint inhibitor to certain patients with high tumor burden, high mutational burden, or mismatch repair deficiency.
Targeted Therapy
- NTRK fusion-positive tumors
- All three guidelines recommend NTRK targeted therapy in the first-line with entrectinib and larotrectinib.
- NCCN also recommends repotrectinib in the first-line.
- Additionally, ASCO recommends NTRK targeted therapy in the subsequent-line for patients who have already been treated with MKIs.
- RET fusion-positive tumors
- All three guidelines recommend RET targeted therapy with selpercatinib in the first-line.
- The NCCN and the ATA also recommend pralsetinib in the first-line.
- Additionally, ASCO recommends RET targeted therapy in the subsequent-line for patients who have already been treated with MKIs.
- ALK fusion-positive tumors
- ALK fusion-positive tumors are rare in thyroid cancers so there is little information on efficacy of ALK targeted therapies.
- The ATA recommends first-line therapy with ALK-targeted therapy (crizotinib, alectinib, and lorlatinib).
- The NCCN suggests that ALK inhibitors may be effective for patients with ALK fusion-positive papillary DTC.
- ASCO did not address systemic therapy for AKL fusion-positive tumors.
- BRAF V600E mutation-positive tumors
- Both the NCCN and ATA have preference for MKI, lenvatinib in the first-line with targeted therapy using dabrafenib and trametinib considered if other alternatives have not been effective or have not been well tolerated.
- ASCO suggests that either targeted therapy with dabrafenib or trametinib, or an MKI may be used in the first-line.
- The NCCN also suggests offering binimetinib/encorafenib for patients with disease progression if there are no other treatment options.
Cytotoxic chemotherapy
- Cytotoxic chemotherapy is not usually offered for DTC.
- The NCCN notes that a relatively small amount of research on its use has shown it to be minimally effective but that pemtrexed/carboplatin may be offered as a subsequent-line therapy for patients with disease progression after other treatments.
- The ATA recommends chemotherapy be used within a clinical trial for patients with metastatic, rapidly progressive, symptomatic, and/or imminently threatening RAIR DTC that cannot be controlled with other therapies.
- ASCO does not recommend cytotoxic chemotherapy as a first-line therapy outside of a clinical trial, but may be used as a subsequent-line therapy for patients with progression on targeted therapy and MKIs.
Comparison of Recommendations
| Category | NCCN | ATA | ASCO |
|---|---|---|---|
| Multi-Kinase Inhibitors (MKIs) | Lenvatinib or sorafenib, lenvatinib is preferred. Cabozantinib may be offered if progression after lenvatinib and/or sorafenib | For patients with progressive RAIR DTC without an actionable biomarker-linked FDA-approved first-line therapy, MKI therapy with either lenvatinib or sorafenib is recommended. In most cases, lenvatinib is the preferred first-line MKI. Cabozantinib should be offered as second-line therapy for patients with RAIR DTC without an actionable oncogenic driver alteration who have progressed on or did not tolerate prior MKI therapy, if they desire ongoing treatment, and do not have a contraindication to therapy. | For patient populations in the first-line setting, clinicians should offer lenvatinib or sorafenib. Although both drugs are approved as first-line options, and despite the lack of direct comparative evidence, lenvatinib would be considered first choice due to the best available efficacy evidence. For patient populations in the subsequent-line setting, clinicians should offer cabozantinib. |
| Immunotherapy | Pembrolizumab may be offered for patients with high tumor burden, high mutation burden, or with mismatch repair deficiency. Pembrolizumab may be added to lenvatinib for patients with disease progression on lenvatinib alone. | Immune checkpoint inhibitors or other forms of immunotherapy may be offered in selected cases, such as when tumors harbor a high tumor mutational burden or are mismatch repair deficient. | For patient populations in the first-line setting, clinicians should not offer immunotherapy outside of a clinical trial. For patient populations in the subsequent-line setting, clinicians may add pembrolizumab to lenvatinib to patients who have disease progression on lenvatinib alone. |
| NTRK Fusion Positive | Entrectinib, larotrectinib, repotrectinib are preferred for NTRK gene fusion-positive tumors. | In patients with progressive RAIR DTC harboring an oncogenic NTRK fusion, NTRK-targeted therapy is recommended in the first line. | For patient populations in the first-line setting, whose tumor harbors NTRK fusions, clinicians should offer genomically targeted therapies, larotrectinib or entrectinib, prior to treatment with MKIs. For patient populations with genomic alterations in the subsequent-line setting, who have been previously treated with MKIs, clinicians should offer NTRK targeted therapies. |
| RET Fusion Positive | Pralsetinib, selpercatinib are preferred for RET fusion-positive tumors. | In patients with progressive RAIR DTC harboring an oncogenic RET fusion, RET-targeted therapy is recommended in the first line. | For patient populations in the first-line setting, whose tumor harbors RET fusions, clinicians should offer genomically targeted therapies, selpercatinib, prior to treatment with MKIs. For patient populations with genomic alterations in the subsequent-line setting, who have been previously treated with MKIs, clinicians should offer RET targeted therapies. |
| ALK Fusion Positive | Patients with papillary carcinoma who have ALK gene fusion may benefit from ALK inhibitors. | In patients with progressive RAIR DTC harboring an oncogenic ALK fusion, anaplastic lymphoma kinase (ALK)-targeted therapy is recommended in the first line. | Not addressed. |
| BRAF V600E Mutation Positive | Preferred therapy is lenvatinib or sorafenib, but lenvatinib is preferred. Patients with disease progression following treatment who have no alternative treatment options may consider dabrafenib/trametinib. Patients with disease progression following treatment who have no alternative treatment options may be offered binimetinib/encorafenib. | In patients with progressive RAIR DTC harboring an oncogenic BRAF V600E mutation, BRAFV600E-directed therapy may be considered in the first line for patients who are poor candidates for lenvatinib. BRAF-directed treatment is recommended in patients with BRAF V600E mutation-positive RAIR DTC who have progressed on or did not tolerate one or more prior MKI therapies. Currently approved BRAF-directed therapies are not recommended in DTCs harboring non-V600 BRAF alterations. | For patient populations in the first-line setting, whose tumor harbors a BRAF V600E mutation, clinicians may offer RET targeted therapies (dabrafenib or trametinib) prior to treatment with MKIs. For patient populations with genomic alterations in the subsequent-line setting, who have been previously treated with MKIs, clinicians should offer genomically targeted therapies (NTRK, BRAF V600E, or RET inhibitors). |
| Cytotoxic Chemotherapy | May consider pemetrexed/carboplatin in patients with disease progression following prior treatment. | Cytotoxic chemotherapy can be considered in patients with RAIR DTC with metastatic, rapidly progressive, symptomatic, and/or imminently threatening disease not amenable to control through other approaches. Use within the context of a therapeutic clinical trial is preferred. | For patient populations in the first-line setting, clinicians should not offer cytotoxic chemotherapy outside of a clinical trial. For patient populations in the subsequent-line setting, who have disease progression on genomically targeted therapies and MKIs, clinicians may offer treatment with cytotoxic chemotherapy. |
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