Phase II trial of sorafenib in advanced thyroid cancer. Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: a prospective analysis of 1056 FNA samples. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population.
PURPOSE Given the molecular pathophysiology of thyroid cancer and the spectrum of kinases inhibited by sorafenib , including Raf kinase , vascular endothelial growth factor receptors , platelet-derived growth factor receptor , and RET tyrosine kinases , we conducted an open-label phase II trial to determine the efficacy of sorafenib in patients with advanced thyroid carcinoma . PATIENTS AND METHODS Eligible patients with metastatic , iodine-refractory thyroid carcinoma received sorafenib 400 mg orally twice daily . Responses were measured radiographically every 2 to 3 months . The study end points included response rate , progression-free survival ( PFS ) , and best response by Response Evaluation Criteria in Solid Tumors . RESULTS Thirty patients were entered onto the study and treated for a minimum of 16 weeks . Seven patients ( 23 % ; 95 % CI , 0.10 to 0.42 ) had a partial response lasting 18 + to 84 weeks . Sixteen patients ( 53 % ; 95 % CI , 0.34 to 0.72 ) had stable disease lasting 14 to 89 + weeks . Seventeen ( 95 % ) of 19 patients for whom serial thyroglobulin levels were available showed a marked and rapid response in thyroglobulin levels with a mean decrease of 70 % . The median PFS was 79 weeks . Toxicity was consistent with other sorafenib trials , although a single patient died of liver failure that was likely treatment related . CONCLUSION Sorafenib has clinical ly relevant antitumor activity in patients with metastatic , iodine-refractory thyroid carcinoma , with an overall clinical benefit rate ( partial response + stable disease ) of 77 % , median PFS of 79 weeks , and an overall acceptable safety profile . These results represent a significant advance over chemotherapy in both response rate and PFS and support further investigation of this agent in these patients CONTEXT Thyroid nodules are common in adults , but only a small fraction of them is malignant . Fine-needle aspiration ( FNA ) cytology provides a definitive diagnosis of benign or malignant disease in many cases , whereas about 25 % of nodules are indeterminate , hindering most appropriate management . OBJECTIVE The objective of the investigation was to study the clinical utility of molecular testing of thyroid FNA sample s with indeterminate cytology . DESIGN Residual material from 1056 consecutive thyroid FNA sample s with indeterminate cytology was used for prospect i ve molecular analysis that included the assessment of cell adequacy by a newly developed PCR assay and testing for a panel of mutations consisted of BRAF V600E , NRAS codon 61 , HRAS codon 61 , and KRAS codons 12/13 point mutations and RET/PTC1 , RET/PTC3 , and PAX8/PPARγ rearrangements . RESULTS The collected material was adequate for molecular analysis in 967 sample s ( 92 % ) , which yielded 87 mutations including 19 BRAF , 62 RAS , 1 RET/PTC , and five PAX8/PPARγ . Four hundred seventy-nine patients who contributed 513 sample s underwent surgery . In specific categories of indeterminate cytology , i.e. atypia of undetermined significance /follicular lesion of undetermined significance , follicular neoplasm/suspicious for a follicular neoplasm , and suspicious for malignant cells , the detection of any mutation conferred the risk of histologic malignancy of 88 , 87 , and 95 % , respectively . The risk of cancer in mutation-negative nodules was 6 , 14 , and 28 % , respectively . Of 6 % of cancers in mutation-negative nodules with atypia of undetermined significance /follicular lesion of undetermined significance cytology , only 2.3 % were invasive and 0.5 % had extrathyroidal extension . CONCLUSION Molecular analysis for a panel of mutations has significant diagnostic value for all categories of indeterminate cytology and can be helpful for more effective clinical management of these patients AIM To evaluate the tolerability and efficacy of sorafenib in patients with thyroid carcinoma . METHODS Patients with progressive locally advanced/metastatic medullary thyroid carcinoma ( MTC ) , or differentiated thyroid carcinoma ( DTC ) with non-radioiodine-avid disease , were treated with sorafenib 400 mg twice daily until disease progression . The primary endpoint was the radiological response rate ( RR ) at 6 months . Secondary endpoints were RR at 3 , 9 and 12 months , biochemical responses , toxicity , biomarker analyses and progression free and overall survival ( OS ) . RESULTS A total of 34 patients were recruited to the study ( 15 medullary and 19 differentiated ) . After 6 months , the RR rate was 15 % and a further 74 % of patients achieved stable disease in the first 6 months . After 12 months of treatment , the RR was 21 % . In the MTC patients , the RR at 12 months was 25 % and OS was 100 % . In DTC patients corresponding rates were 18 and 79 % respectively . Median overall and progression-free survival points were not reached at 19 months . Commonest adverse events included h and -foot syndrome , other skin toxicities , diarrhoea and alopecia . Dose reduction was required in 79 % patients . Median time on treatment was 16.5 months . CONCLUSION This study demonstrates that sorafenib is tolerable at reduced doses over prolonged periods of time in patients with thyroid cancer . Sorafenib leads to radiological and biochemical stabilisation of disease in the majority of these patients despite dose reductions
N early 63,000 new cases of thyroid cancer will be diagnosed in 2014 , with an estimated death rate of 1,900 during this period .
Differentiated thyroid cancer ( DTC ) includes papillary , follicular and Hürthle cell histologies and accounts for greater than 90 % of all thyroid cancers ( American Cancer Society , 2014 ) .
While most differentiated thyroid cancers are curable with implementation of the st and ard of care including surgery , possible radioactive iodine ( RAI ) , and thyroid stimulating hormone ( TSH ) suppression , 10 % to 15 % of patients will have or develop disease that is RAI-refractory or nonavid ( Pacini et al. , 2012 ) .
This population of patients has a poorer prognosis with an overall survival rate of 2.5 to 3.5 years ( Durante et al. , 2006 ) .
For patients who are refractory to RAI and have metastatic or recurrent disease not amenable to surgery or external-beam radiation therapy , there has been a paucity of response to traditional chemotherapeutic agents .
In this setting , cytotoxic agents such as doxorubicin have produced insignificant improvement in objective and subjective sequelae or overall survival benefit ( Gottlieb et al. , 1974 ) .
Thyroid cancer , recognized as highly vascular , also has multiple associated somatic mutations of proto-oncogenes v-Raf murine sarcoma viral oncogene homolog B ( BRAF ) , V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( K-Ras ) , and rearranged during transfection ( RET )