PI PET for response assessment during antiangiogenic TKI therapy in radioiodine-refractory differentiated thyroid cancer: evidence and research priorities

Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) is clinically heterogeneous, and radioiodine refractoriness alone does not mandate immediate systemic therapy. In patients with progressive, symptomatic, or high-burden disease receiving antiangiogenic tyrosine kinase inhibitors (TKIs), contrast-enhanced computed tomography and RECIST remain the principal tools for structural response assessment, yet they may not fully capture early treatment-related changes in the tumor microenvironment. Fibroblast activation protein inhibitor (FAPI) PET has emerged as a candidate imaging approach because fibroblast activation protein (FAP) is abundant in activated tumor-associated stroma. However, while FAPI PET targets FAP-expressing tissues (such as activated cancer-associated fibroblasts), the measured uptake is also influenced by tracer delivery, ligand kinetics, non-malignant fibrosis or inflammation, and acquisition methods. This narrative review critically evaluates whether FAPI PET can serve as a reliable response biomarker during TKI therapy in RAIR-DTC, examining direct clinical data alongside disease-specific diagnostic studies and cross-cancer longitudinal evidence. To date, direct longitudinal evidence during antiangiogenic TKI therapy in RAIR-DTC is limited to a single-patient case report on lenvatinib. Broader thyroid-specific cohorts confirm that FAPI uptake is common in RAIR-DTC, though tracer performance varies substantially by ligand, lesion site, and cohort selection. While cross-cancer studies demonstrate the feasibility of detecting treatment-associated FAPI changes in humans, they do not prove that such changes specifically quantify stromal response or clinical benefit in RAIR-DTC. Moreover, because antiangiogenic therapy directly alters tumor blood flow, vascular permeability, and stromal remodeling, a decrease or increase in FAPI uptake cannot be automatically equated with tumor control or progression. Therefore, the immediate research priority is not clinical implementation, but rather a staged validation process encompassing baseline evaluability, measurement reliability, clinical validity, and ultimately clinical utility beyond standard assessment. Tracer uptake dynamics, actual changes in tissue FAP expression, and true patient benefit should be kept conceptually separate until prospective, outcome-linked validation is achieved.