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Matrone et al. J Cancer Metastasis Treat 2021;7:23 https://dx.doi.org/10.20517/2394-4722.2021.47 Page 3 of 19

measurement of free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH),
is commonly normal, serum CT is elevated, and sometimes this finding can represent the first suspicion of
[34]
the presence of MTC, thus requiring further diagnostic procedures . In advanced cases, carcinoembryonic
antigen (CEA) can also be elevated. CT and CEA also represent the biochemical markers to follow-up MTC
patients after surgery and during local or systemic treatments.

Initial treatment of MTC depends on its clinical presentation. Total thyroidectomy with central
compartment lymph nodes dissection is considered the correct treatment for MTC in the absence of
preoperative evidence of latero-cervical lymph nodes metastases. When during pre- or intra-operative
evaluation latero-cervical lymph nodes metastases are detected, an oriented compartment lymph node
[35]
dissection is advocated . Surgical removal of the primary tumor and lymph nodes metastases of the neck is
[35]
suggested also in cases in which distant metastases are already present . In these latter cases, and in the
case of larger tumors associated to invasion of the vital structure of the neck, in which surgical removal of
the primary tumor and lymph nodes metastases is not feasible, additional therapies should be
performed [36,37] .

The aim of this review is to elucidate the key points about the systemic treatment of advanced, metastatic
MTC. We provide an update of the main aspects of systemic treatment of MTC, focusing the attention on
the drugs which have been developed in the last years, from the tyrosine kinase inhibitors (TKIs) to
radionuclide therapies.

TYROSINE KINASE INHIBITORS
Rationale of treatment
In the last years, several molecular aberrations located in the cell signaling pathways of malignant cells were
discovered. In particular, several tyrosine kinases (TKs), mainly TK receptors (TKRs) involved in cell
growth, differentiation, and angiogenesis, were found to be mutated or overexpressed in tumor cells [38,39] .
The importance of these receptors is linked to the ability of several drugs, named TKIs, to inhibit their
[40]
activity . To date, TKIs are firmly used in the clinical practice for the treatment of several advanced
[41]
tumors, from leukemia to solid tumors [42,43] , including thyroid cancer [36,44-46] . TKIs can act through different
mechanisms: (1) through competition with the adenosine triphosphate (ATP) at the binding site of a TKR,
competition with the substrate, or both; and (2) in an allosteric modality by binding to a site located outside
the active site, thus affecting its activity by determining a conformational change of the kinase [44,47,48] .
Moreover, TKIs can act on tyrosine, serine, threonine, or even histidine residues, therefore are able to
simultaneously inhibit the action of one or more kinases, although with different binding affinities [40,49] .

Several genetic alterations, leading to dysregulation of multiple signaling pathways, have been reported in all
thyroid cancers . TKIs are designed to mainly interact with altered TKRs, and thus with the two main
[50]
signaling pathways involved in cell growth and proliferation: the mitogen-activated protein (MAP)
kinase/extracellular signal-regulated (ERK) pathway and the phosphatidylinositol-3 kinases
(PI3K)/AKT/mTOR pathway [Figure 1].

TKRs are upstream of the MAPK and PI3K pathways, and mutations or gene fusions at this level can affect
the signaling transduction to the downstream, leading to oncogenic transformation and progression.
Similarly, mutations occurring in the MAPK and PI3K pathways can promote tumorigenesis.

In MTCs, the most common TKR alterations are the gain of function point mutations in the RET oncogene,
[51]
which are responsible for most of the hereditary and 40%-70% of the sporadic cases of MTC . The RET