Orbital Radiotherapy for Thyroid-Associated Orbitopathy in the Era of Targeted Biologics: Reposition, Not Replace

Background and Objectives: Orbital radiotherapy (OR) has been used for moderate-to-severe active thyroid-associated orbitopathy (TAO) for decades, yet its role is repeatedly questioned. Sham-controlled randomized trials have not demonstrated a benefit of OR on proptosis or soft-tissue change, whereas clinical practice guidelines continue to recommend OR, combined with glucocorticoids, as a second-line option, particularly for diplopia and restricted ocular motility. The insulin-like growth factor 1 receptor (IGF-1R) inhibitor teprotumumab, with marked effects on proptosis and diplopia, has prompted some to regard OR as obsolete. This review aims to reconcile the long-standing discordance between randomized-trial evidence and guideline recommendations and to reposition OR within the contemporary, biologics-inclusive treatment algorithm. Materials and Methods: We performed a semi-systematic narrative review of PubMed and Embase (inception to June 2026), prioritizing randomized controlled trials, comparative and large observational studies, current guideline and consensus documents, and recent systematic reviews and meta-analyses across radiobiology, dose and technique, efficacy, glucocorticoid combination, safety, health economics, and biologics. Results: The randomized endpoints that failed (proptosis and soft-tissue swelling) are not those that OR is mechanistically expected to improve, whereas its benefit for motility and diplopia aligns with the indication guidelines specified; meta-analyses support a motility and combination benefit. Against teprotumumab, OR shows a smaller proptosis effect but established long-term safety, wide accessibility, and far lower cost, while teprotumumab's real-world durability is limited and its cost and adverse-event burden is substantial. Conclusions: OR is best understood not as a competitor to be replaced but as an accessible, low-cost, motility-directed modality with real limitations of its own (a modest effect on proptosis and a frequent residual need for surgery), whose optimal sequencing alongside glucocorticoids and biologics has yet to be defined by head-to-head and cost-effectiveness studies.