Objective: We conducted a prospective phase II clinical trial to determine the efficacy of sorafenib in patients with advanced radio-iodine refractory differentiated thyroid cancer. In this article, the long-term results are presented. Patients and methods: Thirty-one patients with progressive metastatic or locally advanced radioactive iodine refractory differentiated thyroid cancer received sorafenib 400 mg orally twice daily. The study end points included response rate, progression-free survival (PFS), overall survival (OS), best response by Response Evaluation Criteria in Solid Tumors criteria 1.0, and toxicity. Results: Median PFS was 18 months (95% confidence interval (95% CI): 7-29 months) and median OS was 34.5 months (95% CI: 19-50 months). Eight patients (31%) achieved a partial response and 11 patients (42%) showed stable disease after a median follow-up of 25 months (range 3.5-39 months). Toxicity mostly included hand foot syndrome, weight loss, diarrhea, and rash. Conclusion: Sorafenib has clinically relevant antitumor activity in patients with progressive metastatic or locally advanced radio-iodine refractory differentiated thyroid cancer. Sorafenib can nowadays be considered as the standard option in these patients.

Everolimus has clinically relevant antitumor activity in patients with advanced differentiated thyroid cancer. Given the observed disease control rate and the relatively low toxicity profile, further investigation of everolimus in sequential or combination therapy in these patients is warranted.

The developments in the treatment of advanced thyroid cancer are intriguing. Future trials should aim at combinations of targeted agents with or without other treatment modalities, and will hopefully contribute to further improvement of outcomes.

Objective. Until recently, advanced medullary thyroid cancer (MTC) had few treatment options except surgery. The mTOR inhibitor everolimus has shown encouraging results in neuroendocrine tumors. As part of a prospective phase II study, we analyzed the safety and efficacy of everolimus in advanced MTC. Methods. Seven patients with per RECIST 1.1 documented advanced MTC were included and received everolimus 10 mg daily. The primary objective was determining treatment efficacy. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and pharmacokinetics (PK). Results. Median follow-up duration was 28 weeks (17–147). Five patients (71%) showed SD, of which 4 (57%) showed SD >24 weeks. Median PFS and OS were 33 (95%CI: 8–56) and 30 (95%CI: 15–45) weeks, respectively. Toxicity was predominantly grade 1/2 and included mucositis (43%), fatigue (43%), and hypertriglyceridemia (43%). Four MTCs harbored the somatic RET mutation c.2753T>C, p.Met918Thr. The best clinical response was seen in a MEN2A patient. PK characteristics were consistent with phase I data. One patient exhibited extensive toxicity accompanying elevated everolimus plasma concentrations. Conclusions. This study suggests that everolimus exerts clinically relevant antitumor activity in patients with advanced MTC. Given the high level of clinical benefit and the relatively low toxicity profile, further investigation of everolimus in these patients is warranted.

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