From the Guidelines
Theranostics, particularly those targeting fibroblast activation protein (FAP), represent a promising approach for managing radioiodine-refractory differentiated thyroid cancer (RAI-R DTC), offering personalized treatment options with significant clinical benefits, including disease stabilization and partial responses in a substantial proportion of patients. The integration of diagnostic imaging and molecularly targeted radionuclide therapy in theranostics allows for the identification of tumor-specific targets and the delivery of therapeutic agents that selectively bind to these targets, enabling precise treatment. Three main molecular targets are currently being explored: somatostatin receptors (SSTRs), prostate-specific membrane antigen (PSMA), and fibroblast activation protein (FAP).
Molecular Targets in Theranostics
- Somatostatin receptors (SSTRs) can be detected using 68Gallium-DOTATATE PET imaging, and when high uptake is observed, treatment with 177Lutetium-DOTATATE (PRRT) may be offered, showing disease stabilization and partial responses in 10-30% of patients with disease control rates approaching 60% 1.
- Prostate-specific membrane antigen (PSMA) represents another target, with 68Ga-PSMA-11 PET imaging showing detection rates of 25-100% in metastatic thyroid cancer. Therapeutic applications using 177Lu-PSMA and 225Ac-PSMA are being investigated in early trials.
- Fibroblast activation protein (FAP) is the third promising target, with 68Ga-FAPI PET/CT demonstrating superior sensitivity compared to traditional 18F-FDG PET/CT. Therapeutic applications using 177Lu-DOTAGA.(SA.FAPi)2 have shown clinical benefit in 92% of treated patients who had exhausted standard therapies, with 23% achieving complete response 1.
Therapeutic Applications and Outcomes
Therapeutic applications using FAP-targeted therapies have demonstrated significant clinical benefits. For instance, 177Lu-EB-FAPI has demonstrated partial responses in 25% of patients with stable disease in 58%. These outcomes underscore the potential of FAP-targeted radionuclide therapy in the management of RAI-R DTC, especially in patients who have limited therapeutic alternatives.
Ongoing Research and Future Directions
Ongoing research aims to refine theranostic protocols by optimizing radioligand selection, integrating imaging with treatment workflows, and exploring combination strategies with other treatments, such as tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors. Emerging proteogenomic tools may further enhance patient selection for these targeted approaches, potentially leading to improved outcomes in terms of morbidity, mortality, and quality of life for patients with RAI-R DTC.
From the Research
Theranostics in Radioiodine Refractory DTC
Theranostics has emerged as a promising approach in the management of radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). This strategy relies on molecular imaging to identify tumor-specific targets and deliver therapeutic agents that selectively bind to these targets, enabling personalized and precise treatment.
Molecular Targets for Theranostic Application
Several molecular targets are being actively explored for theranostic application in RAI-R DTC, including:
- Somatostatin receptor (SSTR), which is often overexpressed in oncocytic carcinoma, poorly differentiated thyroid carcinoma, and occasionally in other DTC subtypes 2, 3, 4
- Prostate-specific membrane antigen (PSMA), which is expressed in the tumor-associated vasculature of various solid tumors, including thyroid malignancies 5, 6
- Fibroblast activation protein (FAP), which is expressed by cancer-associated fibroblasts in the tumor microenvironment 3, 6
Theranostic Strategies
Theranostic strategies for RAI-R DTC include:
- Peptide receptor radionuclide therapy (PRRT) using 177Lutetium-DOTATATE, which has shown disease stabilization and partial responses in select patients 2, 3, 4
- Radiolabeled PSMA ligands, such as 177Lu-PSMA and 225Ac-PSMA, which are being investigated in early-phase trials for their potential therapeutic use in RAI-R DTC 5, 6
- FAPI-based imaging and therapy, which has demonstrated high lesion-to-background ratios in RAI-R DTC and potentially identifies lesions not visualized on 18F-FDG or 68Ga-DOTATATE PET/CT 3, 6
Clinical Studies and Outcomes
Clinical studies have demonstrated that PRRT can lead to disease stabilization and partial responses in select patients with RAI-R DTC. A systematic review reported partial response rates of 10%–30% and disease control rates approaching 60% in advanced thyroid cancers with SSTR expression 2. Additionally, FAPI-based therapy has shown promising results, with 92% of treated patients experiencing clinical benefit and 23% achieving complete response 3.