Abstract
This review aims to comprehensively summarize the current role of radioactive iodine (RAI) therapy, organ-based local approaches, and molecular targeted systemic therapies in metastatic differentiated thyroid cancer (DTC). The definition of radioiodine-refractory disease, the impact of tyrosine kinase inhibitors (lenvatinib, sorafenib, cabozantinib) and mutation-specific agents (selpercatinib, larotrectinib) on progression-free survival, and the theranostic perspective are evaluated in detail. Management algorithms, including active surveillance and compartment dissection for locoregional recurrences; the prognostic significance of parenchymal involvement patterns (micro- vs. macronodular) in pulmonary metastases; and multimodal strategies for skeletal metastases involving surgery, stereotactic body radiotherapy, and bone-modifying agents (denosumab, zoledronic acid) to prevent skeletal-related events that are presented in light of the updated American Thyroid Association 2025 and European Association of Nuclear Medicine/Society of Nuclear Medicine and Molecular Imaging guidelines. Furthermore, the role of fluorodeoxyglucose positron emission tomography/computed tomography within the context of the “flip-flop” phenomenon, redifferentiation protocols (mitogen-activated protein kinase/proto-oncogene serine/threonine protein kinase inhibition), emerging theranostic targets such as fibroblast activation protein inhibitor and prostate-specific membrane antigen, and the clinical potential of alpha-emitting radionuclide (astatin-211) therapies are discussed. The integration of organ-based scenarios and molecular characterization in metastatic DTC management will form the basis for personalized treatment strategies and curative-intent multidisciplinary approaches in the future.
Keywords:
Metastatic thyroid cancer, RAI, I-131, RAIR-DTC, lenvatinib, theranostics, ATA 2025, FAPI, PSMA, astatin-211
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