*4.1. Antiangiogenic Therapy*

As previously shown, neo-angiogenesis is a main hallmark of cancer, sustaining its limitless growth [113]. Accordingly, neoplastic cells regulate neo-angiogenesis in order to guarantee their progression in ATC as well as in PDTC [114,115]. Many anti-angiogenic drugs have been employed to inhibit ATC and PDTC growth. Year by year, sorafenib, lenvatinib, cabozantinib, pazopanib, gefitinib and imatinib have been used with fluctuating results.

Sorafenib was the first anti-angiogenic drug proposed for ATC treatment. It was employed in two different phase-2 trials [116,117]; in both of them, disease control (partial response and stable disease) was reached in about 40% of patients but the median overall survival was still lower than 5 months [116,117]. Similarly, sorafenib seemed not to produce exciting results in PDTC [118]. From 2009 to 2011, 40 patients with PDTC were randomly allocated to sorafenib and placebo arms in a randomized, double-blind, multicentric, phase-3 trial (DECISION trial). Although not statistically significant, the sub analysis on PDTC showed a consistent improvement of PFS in patients treated with sorafenib as in all the other histotypes [119]. As reported in DECISION trial, sorafenib toxicity is mainly characterized by grade 1 and grade 2 adverse events such as hand–foot skin reaction, diarrhoea, alopecia, rash/desquamation, fatigue, weight loss, and hypertension [119].

Lenvatinib had very promising results in in-vitro and in-vivo models of ATC that were partially confirmed in clinical settings [120]. Takahashi et al. performed a phase II clinical trial, showing an overall survival of 10.6 months (95% CI: 3.8–19.8) and disease control in 16 out of 17 patients [121]. However, different results were given by a recent post-marketing observational study which reviewed 124 patients affected by ATC and treated with lenvatinib [122]. It showed a disease control in 76.2% (66.89–83.96%) of patients; however, this response seemed to be only transient, because the time-to-treatment failure was 74.5 (57.0–108.0) days, and the median overall survival was still poor (3.4, 95% CI 2.66–4.33 months) [122]. At the same time, baseline clinical conditions of enrolled patients were poor (ECOG > 1) in more than 70% and this could partially explain these disappointing findings. Further studies should be employed in order to verify lenvatinib efficacy in ATC patients with better clinical conditions. Otherwise, lenvatinib produced interesting results for PDTC patients. In SELECT trial, which explored lenvatinib efficacy in patients with radioiodine-refractory thyroid cancer, 28 patients harboring PDTC were enrolled. In this selected population, lenvatinib confirmed its efficacy compared to placebo (HR 0.21, 0.08–0.56) [123]. Accordingly, a retrospective multicentric analysis of real-world data confirmed these encouraging results [124]. In this analysis of clinical practice in Austria enrolling 43 patients, the overall survival seemed to be not modified by tumor subtype (differentiated vs. poorly differentiated/anaplastic TC), whereas a maintenance dosage higher than 14 mg was associated with better prognosis [124]. About toxicity, in spite of high proportion of adverse events with grade ≥ III in SELECT trial (75.9%), Austrian, Italian, and French real-world data reported lower rates of adverse events of grade ≥ III (44%, 22.3% and 48%, respectively) [123–126]. Fatigue, hypertension, diarrhea, decreased weight, stomatitis, and anorexia are the most common reported adverse events [125,126].

More recently, cabozantinib has been explored as a salvage therapy for patients with radioiodine-refractory thyroid cancer already treated with MKIs. In this trial, 7 patients with PDTC were enrolled to receive cabozantinib and all of them presented clinical benefit (3 PR and 4 SD) [127]. Other antiangiogenic agents (pazopanib, gefitinib and imatinib) were employed for ATC therapy but they did not produce encouraging results [128–130].
