Abstract:

Thyroid cancer (TC) is a common malignant tumor of the endocrine system, with differentiated TC (DTC) accounting for more than 90%. Most patients usually have a good overall prognosis after receiving radioactive iodine (RAI) treatment, however some patients’ lesions gradually lose the ability to take up iodine during treatment and become RAI-refractory DTC (RAIR-DTC), with a poor prognosis. For RAIR-DTC recurrence lesions or distant metastases that cannot be surgically removed, it was previously believed that there were limited treatment options. With a deeper understanding of the pathogenesis of RAIR-DTC and its changes at the biomolecular level, targeted therapy, immunotherapy and combined targeted and immune therapy have shown broad application prospects. Their effectiveness and safety have also been confirmed in human studies, bringing new hope for the treatment of RAIR-DTC. This article summarized the pathogenesis and development mechanism of RAIR-DTC, the current status of clinical research on targeted therapy and immunotherapy, and their main conclusions, in order to provide direction for future research. Multi-kinase inhibitors (MKIs) are the first-line therapy for advanced metastatic RAIR-DTC. Currently, Food and Drug Administration (FDA) of the United States has approved the following drugs for the treatment of RAIR-DTC: sorafenib, lenvatinib and cabozantinib. The first two of these have been approved by China National Medical Products Administration for RAIR-DTC treatment. In China, anlotinib and donafenib have also been approved for RAIR-DTC treatment. The efficacy and safety of these targeted therapies have been verified. Apatinib, an anti-angiogenesis inhibitor independently developed in China, is expected to be an effective salvage therapy for sorafenib-resistant lesions. Selective single-target inhibitors, with their more specific action targets, generally cause fewer side effects. For certain RAIR-DTC patients with specific mutation types, selective single-target inhibitors may be more effective. TC is generally considered to have a low tumor mutational burden (TMB), and its response to immunotherapy was once thought to be limited. Immune checkpoint inhibitors (ICIs), including pembrolizumab, durvalumab, atezolizumab and ipilimumab, have shown limited efficacy when used alone. However, when combined with targeted therapy, pembrolizumab can enhance the efficacy of targeted drugs, serving as a viable salvage therapy, potentially due to the “synergistic effect” of the combination therapy. It is crucial to determine the individual contributions of each therapy to tumor suppression and survival extension, especially when the sample size is limited. The design of reasonable controls becomes the key in these studies. Previous studies were obstructed by the unclear definition of RAIR-DTC, limited sample sizes and high heterogeneity. Therefore, prospective, multi-center, large-scale clinical trials are needed in the future. Additionally, it is essential to consider whether prolonged progression-free survival (PFS) after treatment can be translated into long-term survival benefits, and whether it improves the quality of life for patients. In conclusion, the treatment of RAIR-DTC still faces many challenges, we must continue to explore and address these issues in the future.

Key words: Radioiodine-refractory differentiated thyroid cancer, Gene mutation, Signaling pathway, Immune microenvironment, Targeted therapy, Immunotherapy, Combination therapy, Prognosis