**4. Multi-kinase and angiogenetic factor inhibitors**

The successful application of multi-kinase and angiogenetic factor inhibitors in the treatment of various types of cancer [25] has led to observations that multiple kinase and angiogenetic factor inhibitors attack the thyroid cells and may lead to hypothyroidism and in some cases eradication of the thyroid gland [27, 28, 47]. These observations led to the application of multi-kinase and angiogenetic factor inhibitors in the treatment of radioactive iodine refractory and advanced thyroid cancer (**Table 1**) [37]. Multi-kinase and angiogenetic factor inhibitors interfere with some of the pathogenetic pathways involved in the pathogenesis of thyroid cancer and in tumor growth and the development of metastatic disease [10]. This application has led to a revolution in the treatment of advanced thyroid cancer.


*TKI—tyrosine kinase inhibitor, STKI—serine-threonine kinase inhibitor, DTC—differentiated thyroid cancer, MTC medullary thyroid cancer, ATC—anaplastic thyroid cancer.*

#### **Table 1.**

*Drugs applied in the treatment of advanced thyroid cancer.*

#### **4.1 Sunitinib**

Sunitinib is a small molecule and is a multi-kinase and angiogenetic factor inhibitor that inhibits RET/PTC subtypes 1 and 3, VEGFR1, VEGFR-2, VGEFR-3, KIT, and PDGFR kinases [48]. The drug was initially approved by the FDA for gastrointestinal stromal tumor and clear cell renal carcinoma [49]. The drug is currently under investigation for the treatment of several human tumors. The most common adverse events are hand-foot syndrome, fatigue, neutropenia, diarrhea, hypothyroidism, and hypertension [50].

Sunitinib was found in preclinical studies to inhibit *in vitro* RET/PTC oncoproteins. It has been studied in various studies in differentiated thyroid cancer and medullary thyroid cancer patients and either partial response or stable disease was observed [51, 52]. In a study with metastatic radioiodine-refractory thyroid cancer partial response was observed. In the phase II trial of sunitinib (THYSU), the drug was tested in patients with advanced or metastatic differentiated/anaplastic or medullary thyroid cancer with improvement in progression-free survival and overall survival [53, 54]. In the phase II trial of sunitinib in progressive medullary thyroid cancer patients, the drug was found to be effective in progressive medullary thyroid cancer. In an open-label phase II study, sunitinib was found to induce complete response in some patients with metastatic medullary thyroid cancer and differentiated thyroid cancer. In an anaplastic thyroid cancer patient, sunitinib was administered with a good clinical response [55].

#### **4.2 Sorafenib**

Sorafenib is a multi-kinase inhibitor that inhibits RAF, VEGFR2, VEGFR3, PDGFR, RET, and KIT kinases [56, 57]. It exerts anti-neoplasmatic effects in preclinical models of cancer and thyroid cancer cell lines. Sorafenib inhibits thyroid cancer growth by acting with antiproliferative and antiangiogenic mechanisms [57]. The FDA has approved its use in hepatocellular and renal cell carcinoma and metastatic differentiated thyroid carcinoma [58]. Sorafenib is administered orally at 400 mg twice daily and is usually well tolerated. Sorafenib has been administered to patients with metastatic radioiodine refractory thyroid cancer for about 27 weeks and it was found to induce a partial response, improve progression-free survival and have clinical benefits [59]. In another study, sorafenib was administered to patients with metastatic papillary thyroid cancer chemotherapy-naive and in patients with papillary thyroid cancer who had already received chemotherapy and other subtypes of thyroid cancer and it was found to induce partial response in 6 of 22 patients and to induce disease stabilization which lasted more than 6 months in 23 patients [59, 60]. Sorafenib was administered to radioactive iodine refractory papillary and follicular thyroid cancer with a remission rate of 20% [59]. In these patients with metastatic thyroid cancer, the response of metastatic disease differed depending on the site of metastasis. Bone lesions had a minimal response, whereas a better effect was observed in lung metastatic disease. Thyroglobulin was considered a positive biomarker of response to treatment. In a double-blind phase III trial, the clinical activity of sorafenib as compared to placebo was assessed in patients with radioactive iodine refractory locally advanced or metastatic differentiated thyroid carcinoma [17]. In patients treated with sorafenib, the progress-free survival increased in all subgroups regardless of mutation status. This study demonstrated the efficacy of sorafenib in radioactive–iodine refractory differentiated thyroid cancer. Other studies demonstrated the efficacy of sorafenib in progressive metastatic differentiated thyroid cancer. A meta-analysis involving 15 studies evaluated the safety and efficacy of sorafenib in radioactive iodine refractory differentiated thyroid carcinoma [59]. Sorafenib improved progression-free survival in patients with radioactive iodine refractory differentiated thyroid carcinoma patients. The most frequent adverse effects were hand-foot syndrome, diarrhea, fatigue, alopecia, weight loss, and rash. The study focused on the efficacy of sorafenib in improving progression-free survival in differentiated thyroid cancer as compared to placebo. Although sorafenib was observed in combination with metformin to inhibit anaplastic thyroid cancer cells [61], the drug was not effective *in vivo* in an anaplastic thyroid cancer patient [36].

Sorafenib is associated with an increase in progression-free survival and disease stabilization. Sorafenib administration and acquired resistance to it may be associated with the induction of autophagy [62]. In this context, several substances have been applied to limit autophagy and the related resistance of cancer to treatment [62, 63]. The administration of agents to inhibit autophagy may sensitize a tumor to the multikinase inhibitor linifanib [64].

#### **4.3 Vandetanib**

Vandetanib is a potent inhibitor of VEGFR-2, VEGFR-3, RET, and EGFR kinases [65]. Vandetanib has been approved by FDA and EMA for use in patients with

metastatic or progressive medullary thyroid cancer [66]. In an international randomized trial, the therapeutic efficacy of vandetanib was shown in patients with advanced medullary thyroid cancer as it showed a significant prolongation of progression-free survival as compared to placebo [67]. In a double-blind phase II study, vandetanib was shown to prolong progression-free survival in patients with locally advanced or metastatic differentiated thyroid carcinoma patients [68]. Recently, a meta-analysis and systematic review, through standardized RECIST criteria as endpoints, investigated vandetanib efficacy in medullary thyroid carcinoma. The study included only original studies in which the drug was used as a single agent. Ten (eight observational longitudinal studies and two randomized controlled trials) were included among the 487 screened articles. The results obtained through the RECIST criteria did not provide clear evidence of the efficacy of vandetanib [69]. Nonetheless, vandetanib is considered a new-generation treatment in advanced medullary thyroid carcinoma.

Vandetanib has been evaluated in patients with symptomatic or progressive medullary thyroid cancer in various starting doses, 150 or 300 mg daily, and was found to have a good response with a better response at the dose of 300 mg [70]. Adverse effects of vandetanib were QTc prolongation, hypocalcemia, asthenia, diarrhea, keratopathy, and hypokalemia. In a systematic review, the cost-effectiveness of cabozantinib and vandetanib were compared [71]. Both drugs improved progress-free survival although no significant overall survival benefits were observed. Vandetanib is considered a new-generation treatment for advanced medullary thyroid cancer.

#### **4.4 Lenvatinib**

Lenvatinib inhibits FGFR-1, FGFR-2, FGFR-3, FGFR-4, PGGFRβ, VEGFR-1, VEGFR-2, VEGFR-3, RET, and KIT kinases [72]. Lenvatinib has been approved by FDA and EMA for the treatment of advanced radioactive iodine refractory differentiated thyroid cancer [73]. Lenvatinib was administered to patients with advanced radioiodine refractory differentiated thyroid cancer that had progressed during the earlier 12 months. After a follow-up of 14 months, the overall response rate was 50%, the median time to relapse was 3.6 months, the median progression-free survival was 12.6 months and the median response duration was 12.7 months. Lenvatinib was administered to patients with unresectable progressive medullary thyroid cancer and was found to be effective [74]. In a double-blind randomized study, lenvatinib was administered to 261 patients with progressive radioiodine refractory thyroid carcinoma [16]. The study included a placebo group of 131 patients. Median progressionfree survival was longer in the lenvatinib group as compared to placebo. The response rate was 64.8%. However, side effects were observed. In a randomized study examining the effect of lenvatinib on tumor size, it was shown to improve tumor size rapidly at the beginning of the study and to induce continued shrinkage thereafter [75]. A phase II study evaluated lenvatinib in 51 patients with radioactive iodine refractory differentiated thyroid carcinoma, medullary thyroid carcinoma, and anaplastic thyroid cancer with a median progression-free survival of 25.8 months, 9.2 months, and 7.4 months, respectively [76]. The safety profile of the drug was manageable, and an antitumor efficacy was observed in radioactive iodine refractory thyroid cancer and promising efficacy in medullary thyroid cancer and anaplastic thyroid cancer. Lenvatinib was also evaluated postoperatively in anaplastic thyroid cancer patients and was shown to have a response rate of 17.4% [77]. Hypertension was the most frequent adverse effect.
