Approach and Challenges for Patients with Advanced Radioiodine-Refractory Differentiated Thyroid Cancer.

Differentiated thyroid cancers (DTC), 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 (TSH) suppression, and radioactive iodine (RAI) therapy. However, a subset of patients develops radioiodine-refractory (RAI-R) 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. Recent advancements have transformed the treatment landscape with the emergence of systemic therapies such as anti-angiogenic multikinase inhibitors (aaMKIs) and genotype-directed therapies that offer improved disease control in advanced settings. This review consolidates the current evidence for diagnosing, evaluating, and managing advanced RAI-R DTC. 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. 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.