Effects and Role of Multikinase Inhibitors in Thyroid Cancer.
Thyroid cancer is the most common type of endocrine neoplasia. Differentiated thyroid carcinoma (DTC) represents 94% of all thyroid cancer types. Approximately 20% experience local recurrence and 10% distant metastasis. The recurrent DTC often becomes less differentiated, loses the iodine uptake capability and consequently loses the radioactive iodine treatment option. Under these circumstances survivability drops below 10% at 10 years. The treatment options for dedifferentiated thyroid cancers are extremely limited. This category sometimes referred to as poorly differentiated thyroid cancer (PDTC), is characterised by a missing response to radioiodine treatment and a remarkably reduced survivability. Therefore, new drugs have been developed to fill this gap in treatment.



The goal of this work is to review the effects and roles of the multikinase inhibitors sorafenib, sunitinb and lenatinib in thyroid cancer.



The new tyrosine kinase inhibitors (TKIs) aimed to inhibit tumour angiogenesis. Current clinical trials with novel drugs have shown promising results. A phase III trial (DECISION) of sorafenib in radioiodine (RAI)-refractory thyroid cancer showed a median progression-free survival (PFS) of 10.8 months in the sorafenib group, compared to 5.8 months in the placebo group. Sunitinib, another TKI, exhibited significant antitumour effects in patients with advanced DTC. Nevertheless, treatment with TKIs can lead to the development of resistance against these anti-angiogenic treatments, partly due to compensatory mechanisms. Lenvatinib, the recently approved drug for RAI-refractory thyroid cancer, blocks a different receptor than the currently available drugs. Lenvatinib inhibits fibroblast growth factor receptor (FGFR), as well as other receptors. FGFR plays a key role in the development of resistance against anti-angiogenic drugs. In a phase III trial (SELECT) on RAI-refractory DTC, the lenvatinib group showed a PFS of 18.3 months, compared to 3.6 months in the placebo group. This led to the approval of lenvatinib, the first drug capable of reversing anti-angiogenic mechanisms.



The frequently adverse effects seen in TKI treatment require further investigation. A well-adjusted balance between efficacy and adverse effects is desirable. No effects on overall survival were reported. Therefore, further studies are required.
Rasmus
R
Laursen
Markus
M
Wehland
Sascha
S
Kopp
Jessica
J
Pietsch
Manfred
M
Infanger
Jirka
J
Grosse
Institute of Biomedicine, Pharmacology, Aarhus University, Wilhelm Meyers Allé 4, DK-8000 Aarhus C, Denmark.
Daniela
D
Grimm
D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases