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Data from patients with metastatic refractory thyroid cancer who received TKIs from April 2009 to December 2014 were retrospectively analyzed. Approval for the drug administration to every patient was obtained from the insitutional scientific committee and the National Drug Organization. Each patient was informed in detail about the efficacy and possible adverse events (minor or major) associated with the treatment. The same doctor (SM) educated all patients and confirmed their understanding of the possible complications of therapy and its expected efficacy. All patients agreed to start TKI therapy after they had been fully informed and given their written consent.

All patients were of Caucasian origin, of similar socioeconomic status, and lived in Northern Greece (population approximately 3 million inhabitants). Initially, candidates for sunitinib were those who had metastatic DTC to the lungs or bones refractory to iodine treatment and progressive disease within 12 months before baseline, documented by computed tomography (CT) or magnetic resonance imaging (MRI) and thyroglobulin; and for sorafenib were those who had metastatic MTC to the liver (with unresectable metastatic lesions) or bones and progressive disease within 12 months before baseline, documented by CT or MRI and by an increase in serum calcitonin levels. After approval by the European Medicines Agency (EMA) for sorafenib and vandetanib to be used in the treatment of DTC and MTC, respectively, patients with refractory thyroid cancer who were candidates for TKIs received these drugs. All patients were in general good health, defined as an Eastern Cooperative Oncology Group performance status of 0 or 1.11 A clinical evaluation was performed, and normal blood pressure, with appropriate treatment where necessary, was achieved before initiation of TKI treatment. All patients had normal liver, renal, and bone marrow function. No abnormalities were identified on baseline electrocardiography or echocardiography. Baseline QT intervals were in the normal range.

Sorafenib 400 mg was given orally twice daily continuously, sunitinib was given as 50 mg once daily on a 4–2 schedule (4 weeks of treatment followed by 2-week intervals without therapy), and vandetanib was given as 300 mg once daily. A 4-week treatment with each agent defined a cycle. Patients were evaluated weekly for the first cycle and monthly thereafter, in order to determine well-being and Eastern Cooperative Oncology Group performance status. At each visit, clinical examination, blood pressure, weight, and a complete blood count, urinalysis, and serum biochemical measurements were performed. Cardiac evaluation with an electrocardiogram and/or echocardiogram was periodically performed and when indicated according to patient symptoms. Extensive discussion, evaluation of predisposing factors (such as diabetes), and written information was provided regarding the side effects of the medication. Patients were advised to prevent stomatitis with systematic oral care hygiene using a soft toothbrush and bland rinses, and to use local anesthetics as/if needed.12The patients were also asked to limit exposure of the hands and feet to hot water, chemicals, or sources of heat (eg, sitting in the sun), to take cool showers, wear well-ventilated shoes, and apply skin care creams to keep the hands moist in order to prevent and manage hand-foot syndrome.13Patients were instructed to report any new symptom or sign to their physicians at every visit.

Answers to questions regarding changes in daily habits were recorded. Any adverse events were documented and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.14 The presence of adverse events that would need dose reduction or discontinuation of therapy was also documented at every visit.

Response to therapy was estimated by CT or MRI after three and six cycles and every four cycles thereafter. Disease progression was assessed according to the Response Evaluation Criteria in Solid Tumors (version 1.0).15 Thyroid-stimulating hormone (TSH) for all patients, thyroglobulin for DTC patients, and calcitonin for MTC patients were also evaluated concomitantly. The study was approved by the institutional review board. The presented data are expressed where appropriate as the median and range.