Abstract:

Most patients with differentiated thyroid cancer benefit from surgery, radioactive iodine-131 therapy and TSH suppression therapy, resulting in a favorable prognosis. However, once radioactive iodine refractory thyroid cancer (RAIR-DTC) develops, the prognosis becomes significantly poorer, treatment options are limited, and therapeutic efficacy is constrained. This has emerged as a research focus in recent years. With advancements in understanding tumor mechanisms and rapid developments in diagnostic and therapeutic technologies, significant progress has been made in new drugs and new treatments for RAIR-DTC. The development of novel targeted therapies has revolutionized the management. Notably, multi-target tyrosine kinase inhibitor (mTKI) such as sorafenib and lenvatinib has demonstrated significant improvements in progression-free survival, thereby establishing targeted therapy as a viable option for RAIR-DTC. Cabozantinib has also shown promising results as a second-line treatment following TKI failure. Other TKIs like apatinib and anlotinib have also arnered attention due to efficacy and safety. Additionally, specific TKI targeting BRAF V600E mutations, RET fusions and NTRK fusion genes have ushered in an era of precision medicine for RAIR-DTC. Thus, for patients with RET or NTRK fusions, guidelines recommend prioritizing specific target TKI over pan-target kinase inhibitors. If no such gene mutations are present, pan-target kinase inhibitors are considered as the standard first-line treatments. MEK inhibitors (selumetinib) may induce redifferentiation, potentially restoring iodine uptake. Consequently, the combination of targeted therapy and iodine-131 therapy represents a promising strategy. While immune checkpoint inhibitors only have not yielded optimistic results in RAIR-DTC, combination with TKIs has shown certain safety and efficacy, warranting further exploration. However, given issues of drug resistance and intolerable side effects, it is imperative to explore new treatments. Radionuclide therapy guided by nuclear medicine molecular imaging offers potential hope for RAIR-DTC patients. Targeted radioligand/receptor therapies, such as PSMA, SSTR and FAPi, exhibit characteristics of targeting, visualization and integration of diagnosis and treatment. Initial trials of them in RAIR-DTC patients with TKIs treatment failure have been confirmed feasibility. This review summarized recent advances in new drugs and new technologies for RAIR-DTC treatment, aiming to guide clinical practice and anticipate more personalized and precise treatment options to improve quality of life and survival.

Key words: Radioactive iodine refractory, Differentiated thyroid cancer, Targeted therapy, Immunotherapy, Radionuclide therapy, Tyrosine kinase inhibitor