Volume 32, Issue 2, February 2026, Pages 268-279Author links open overlay panel, , AbstractObjective

Differentiated thyroid cancers (DTCs), including papillary, follicular, and oncocytic subtypes, are generally associated with an excellent prognosis due to their responsiveness to conventional therapies, including surgery, thyroid-stimulating hormone suppression, and radioactive iodine (RAI) therapy. However, a subset of patients develops RAI-refractory disease, characterized by tumor dedifferentiation and loss of iodine avidity, resulting in disease progression despite standard interventions. This group poses a considerable therapeutic challenge and is associated with markedly poorer outcomes. This review summarizes contemporary approaches to advanced RAI-refractory DTC.

Methods

This review consolidates the current evidence for diagnosing, evaluating, and managing advanced RAI-refractory DTC.

Results

Recent advancements have transformed the treatment landscape with the emergence of systemic therapies such as antiangiogenic multikinase inhibitors and genotype-directed therapies that offer improved disease control in advanced settings. It explores the pathophysiological basis of refractoriness, prognostic implications, treatment selection strategies—including active surveillance, locoregional therapies, redifferentiation approaches, and systemic therapies—and outlines practical considerations for clinicians.

Conclusion

Future directions including immunotherapy, novel agents, and personalized therapy strategies are also discussed. Emphasis is placed on precision oncology, toxicity management, and the role of multidisciplinary care in optimizing patient outcomes.

Key words

cabozantinib

differentiated thyroid cancer

lenvatinib

multikinase inhibitors

precision oncology

radioiodine refractory

sorafenib

systemic therapy

targeted therapy

thyroid cancer

AbbreviationsaaMKI

anti-angiogenic multikinase inhibitor

CAR-T

chimeric antigen receptor T-cell

DTC

differentiated thyroid cancer

FAP

fibroblast activation protein

FTC

follicular thyroid cancer

HER2

human epidermal growth factor receptor 2

MAPK

mitogen-activated protein kinase

mTOR

mammalian target of rapamycin

NIS

sodium-iodide symporter

NTRK

neurotrophic tyrosine receptor kinase

ORR

objective response rate

PET

positron emission tomography

PFS

progression-free survival

PI3K

phosphatidylinositol 3-kinase

PTC

papillary thyroid cancer

RAI-R DTC

radioactive iodine-refractory differentiated thyroid cancer

TERT

telomerase reverse transcriptase

TSH

thyroid-stimulating hormone

VEGFR

vascular endothelial growth factor receptor

View Abstract

Published by Elsevier Inc. on behalf of the AACE.