**Abstract**

The standard treatment for patients with differentiated thyroid cancer (DTC) is a combination of surgery, radioactive iodine (RAI), and long-term thyroid hormone–suppression therapy. Treatment of patients whose diseases persist, recur, or metastasize remains a challenge. The role of cytotoxic chemotherapy in the treatment of thyroid cancer is limited. The key signaling pathways involved in the pathogenesis of thyroid cancers are the RAS/RAF/MEK & PI3K/Akt/mTOR pathways. Systemic therapy in thyroid cancer involves the use of tyrosine kinase inhibitors targeting the above mentioned pathways which are often both effective in controlling disease and have manageable toxicity. Sorafenib and lenvatinib are approved for advanced radioiodine refractory and poorly differentiated thyroid cancers and vandetanib and cabozantinib for recurrent or metastatic medullary thyroid cancers. Cabozantinib is also approved for the treatment of locally advanced or metastatic radioactive iodine–refractory differentiated thyroid cancer that has progressed after prior VEGF-targeted therapy. The combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) is approved for BRAF V600E mutated unresectable locally advanced anaplastic thyroid cancer. Selpercatinib, RET kinase inhibitor is used for advanced and metastatic RET mutated medullary thyroid cancers and advanced and metastatic RET fusionpositive thyroid cancers of any histologic type. Various clinical trials using newer molecules targeting the aforementioned pathways are ongoing.

**Keywords:** carcinoma thyroid, Iodine refractory, tyrosine kinase inhibitors, anaplastic and medullary thyroid cancer, differentiated thyroid cancer (DTC)

## **1. Introduction**

The incidence of thyroid cancers is on the rise with over 586,202 new patients diagnosed and greater than 43,646 deaths recorded each year worldwide [1]. Thyroid cancers arise from either of the two cell types, namely follicular and parafollicular cells. Differentiated thyroid cancer (DTC) accounts for 95% of all thyroid cancers [2] and has three subtypes, papillary thyroid cancer (PTC), follicular thyroid cancer

(FTC), and Hurthle cell thyroid cancer (HCTC). The poorly differentiated or undifferentiated category includes anaplastic thyroid cancer (ATC). Differentiated and undifferentiated tumors originate in follicular cells and medullary thyroid cancer (MTC) arises from parafollicular or C cells. While surgery remains the mainstay of the treatment of all different histologies of thyroid cancers, for differentiated thyroid cancers, radioactive iodine and TSH suppression therapy also play an important role in adjuvant management [3]. The prognosis of thyroid cancer, with the exception of anaplastic thyroid cancer is excellent with the standard therapy. Treatment of patients whose diseases persist, recur, or metastasize remains challenging. Cytotoxic chemotherapy has limited role in the treatment of thyroid cancer, hence there was an urgent need for the development of new more effective therapies for that subset of patients. Recent developments in understanding the molecular etiologies of thyroid cancer have led to the identification of novel precision oncological treatments that are significantly improving the outlook for patients with advanced diseases and a new era of treatment options emerged. Targeted therapy with kinase inhibitors has shown promise in management of metastatic and recurrent thyroid cancer. This chapter summarizes the rationale for using systemic therapy and the approved drugs in recurrent or metastatic thyroid carcinoma.
