ABSTRACT
Background: Mammalian target of rapamycin (mTOR) upregulation has been reported to be involved in the pathogenesis of thyroid tumors, and treatment with the mTOR inhibitor everolimus has shown promising results in endocrine tumors. We conducted a prospective phase II clinical trial to determine the efficacy and safety of everolimus in patients with advanced follicular-derived thyroid cancer. Patients and Methods: Twenty-eight patients with progressive metastatic or locally advanced radioactive refractory differentiated thyroid cancer and 7 patients with anaplastic thyroid cancer were included and received everolimus 10 mg orally once daily. The primary endpoint was disease control rate [complete (CR) + partial response (PR) + stable disease (SD) > 24 weeks]. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and mutational and pharmacokinetic-related outcomes. Results: Median follow-up duration was 38 months (2-64). Seventeen patients (65%) showed SD, of which 15 (58%) showed SD >24 weeks. No CR or PR was observed. Median PFS and OS were 9 [95% confidence interval (CI): 4 to 14] and 18 (95% CI: 7 to 29) months, respectively. Survival was negatively influenced by the presence of bone metastases. Toxicity was predominantly grade 1/2 and included anemia (64%), cough (64%), stomatitis (61%), and hyperglycemia (61%). Duration of SD was related to everolimus exposure. The presence of somatic gene variants related to mTOR signaling did not clearly stratify for responses. Conclusion: 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.
Subject(s)
Adenocarcinoma, Follicular/drug therapy , Antineoplastic Agents/pharmacology , Everolimus/pharmacology , Outcome Assessment, Health Care , Thyroid Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Everolimus/administration & dosage , Everolimus/adverse effects , Female , Follow-Up Studies , Humans , Male , Middle AgedABSTRACT
BACKGROUND: Sorafenib is an orally active multikinase tyrosine kinase inhibitor (TKI) that targets B-type Raf kinase (BRAF), vascular endothelial growth factor receptors (VEGFR) 1 and 2, and rearranged during transfection (RET), inducing anti-angiogenic and pro-apoptotic actions in a wide range of solid tumors. A side effect of sorafenib is the occurrence of cutaneous squamous tumors. CASE PRESENTATION: Here we describe three patients with a history of sorafenib treatment for advanced radioactive iodine refractory papillary thyroid cancer (two with a BRAF c.1799 T > A and one carrying a rare c.1799-1801het_delTGA mutation) who presented with secondary non-cutaneous lesions. The first patient was diagnosed with a squamous cell carcinoma (SCC) of the tongue, the second patient with a primary adenocarcinoma of the lung, and the third with a SCC originating from the cricoid. Secondary analysis was required to show that the latter two presentations were in fact recurrent thyroid cancer. CONCLUSION: These findings suggest that drugs such as sorafenib may induce metaplasia/clonal divergence of metastatic thyroid cancer and thus cause diagnostic misclassification. Furthermore, sorafenib is potentially involved in the tumorigenesis of secondary non-cutaneous SCC. These observations should now be confirmed in larger series of patients treated with drugs such as sorafenib.
