human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECTIVE Treatment options for patients with radioactive iodine ( RaI ) refractory metastases of differentiated thyroid carcinoma ( DTC ) are limited . We studied the effects of the multitarget tyrosine kinase inhibitor sorafenib on the reinduction of RaI uptake and tumor progression . DESIGN Open , single center , single arm 26-week prospect i ve phase II study with open-ended extension . METHODS We treated 31 patients with progressive metastatic or locally advanced RaI refractory DTC with sorafenib 400 mg b.i.d . The primary endpoint was reinduction of RaI uptake at 26 weeks . Additional endpoints were the radiological response and the influence of bone metastases . RESULTS At 26 weeks of sorafenib therapy , no reinduction of RaI uptake at metastatic sites was observed , but 19 patients ( 59 % ) had a clinical beneficial response , eight of whom had a partial response ( 25 % ) and 11 had stable disease ( 34 % ) . Seven patients had progressive disease ( 22 % ) . Sorafenib was significantly less effective in patients with bone metastases . The estimated median progression free survival was 58 weeks ( 95 % confidence interval , CI , 47 - 68 ) . In general , thyroglobulin ( Tg ) response ( both unstimulated and TSH stimulated ) reflected radiological responses . The median time of the nadir of Tg levels was 3 months . Responses were not influenced by histological subtype , mutational status or other variables . No unusual side effects were observed . CONCLUSIONS Sorafenib has a beneficial effect on tumor progression in patients with metastatic DTC , but was less effective in patients with bone metastases . Diagnostic whole body scintigraphy did not reveal an effect of sorafenib on the reinduction of RaI uptake 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 PURPOSE Cabozantinib , a tyrosine kinase inhibitor ( TKI ) of hepatocyte growth factor receptor ( MET ) , vascular endothelial growth factor receptor 2 , and rearranged during transfection ( RET ) , demonstrated clinical activity in patients with medullary thyroid cancer ( MTC ) in phase I. PATIENTS AND METHODS We conducted a double-blind , phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC . Patients were r and omly assigned ( 2:1 ) to cabozantinib ( 140 mg per day ) or placebo . The primary end point was progression-free survival ( PFS ) . Additional outcome measures included tumor response rate , overall survival , and safety . RESULTS The estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo ( hazard ratio , 0.28 ; 95 % CI , 0.19 to 0.40 ; P < .001 ) . Prolonged PFS with cabozantinib was observed across all subgroups including by age , prior TKI treatment , and RET mutation status ( hereditary or sporadic ) . Response rate was 28 % for cabozantinib and 0 % for placebo ; responses were seen regardless of RET mutation status . Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3 % for cabozantinib and 7.2 % for placebo . Common cabozantinib-associated adverse events included diarrhea , palmar-plantar erythrodysesthesia , decreased weight and appetite , nausea , and fatigue and result ed in dose reductions in 79 % and holds in 65 % of patients . Adverse events led to treatment discontinuation in 16 % of cabozantinib-treated patients and in 8 % of placebo-treated patients . CONCLUSION Cabozantinib ( 140 mg per day ) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease . This dose of cabozantinib was associated with significant but manageable toxicity OBJECTIVE We conducted a prospect i ve 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 h and foot syndrome , weight loss , diarrhea , and rash . CONCLUSION Sorafenib has clinical ly relevant antitumor activity in patients with progressive metastatic or locally advanced radio-iodine refractory differentiated thyroid cancer .  Sorafenib can nowadays be considered as the st and ard option in these patients PURPOSE Ras/Raf/MAPK kinase/ERK and rearranged in transformation ( RET ) kinase pathways are important in thyroid cancer . We tested sorafenib , a B-Raf , RET , and vascular endothelial growth factor receptor kinase inhibitor , combined with tipifarnib , a farnesyltransferase inhibitor that inactivates Ras and other farnesylated proteins . PATIENTS AND METHODS We treated 35 patients with differentiated thyroid cancer ( DTC ) and medullary thyroid cancer ( MTC ) in a phase I trial . Sorafenib and tipifarnib were given for 21 d with 7 d rest in each 28-d cycle . RESULTS We enrolled 22 patients with metastatic DTC ( 16 papillary , five follicular , and one poorly differentiated ) and 13 patients with MTC , of whom 15 with DTC and 10 with MTC reached first restaging . When tissue was available , eight of 15 DTC patients ( 53 % ) had B-Raf mutations ; eight of 13 MTC ( 61.5 % ) patients had RET mutations . MTC partial response rate was 38 % ( five of 13 ) ( duration = 9 + , 12 , 13 , 16 + , and 34 + months ) , stable disease of at least 6 months was 31 % ( four of 13 ) . The DTC partial response rate was 4.5 % ( one of 22 ) , and stable disease of at least 6 months was 36 % ( eight of 22 ) . Median progression-free survival for all 35 patients was 18 months ( 95 % confidence interval , 14.6 to not reached months ) . Median overall survival has not been reached , with a median follow-up of 24 months with 80 % overall survival . Grade 1 - 2 toxicities were mainly rash , fatigue , and diarrhea . The most common grade 3 - 4 toxicities were rash , rise in amylase/lipase , and fatigue . CONCLUSIONS Inhibiting the Ras/Raf/MAPK kinase/ERK and RET kinase pathways with sorafenib and tipifarnib is well tolerated and active against thyroid cancer 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 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECTIVE Treatment options for patients with radioactive iodine ( RaI ) refractory metastases of differentiated thyroid carcinoma ( DTC ) are limited . We studied the effects of the multitarget tyrosine kinase inhibitor sorafenib on the reinduction of RaI uptake and tumor progression . DESIGN Open , single center , single arm 26-week prospect i ve phase II study with open-ended extension . METHODS We treated 31 patients with progressive metastatic or locally advanced RaI refractory DTC with sorafenib 400 mg b.i.d . The primary endpoint was reinduction of RaI uptake at 26 weeks . Additional endpoints were the radiological response and the influence of bone metastases . RESULTS At 26 weeks of sorafenib therapy , no reinduction of RaI uptake at metastatic sites was observed , but 19 patients ( 59 % ) had a clinical beneficial response , eight of whom had a partial response ( 25 % ) and 11 had stable disease ( 34 % ) . Seven patients had progressive disease ( 22 % ) . Sorafenib was significantly less effective in patients with bone metastases . The estimated median progression free survival was 58 weeks ( 95 % confidence interval , CI , 47 - 68 ) . In general , thyroglobulin ( Tg ) response ( both unstimulated and TSH stimulated ) reflected radiological responses . The median time of the nadir of Tg levels was 3 months . Responses were not influenced by histological subtype , mutational status or other variables . No unusual side effects were observed . CONCLUSIONS Sorafenib has a beneficial effect on tumor progression in patients with metastatic DTC , but was less effective in patients with bone metastases . Diagnostic whole body scintigraphy did not reveal an effect of sorafenib on the reinduction of RaI uptake 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 PURPOSE Cabozantinib , a tyrosine kinase inhibitor ( TKI ) of hepatocyte growth factor receptor ( MET ) , vascular endothelial growth factor receptor 2 , and rearranged during transfection ( RET ) , demonstrated clinical activity in patients with medullary thyroid cancer ( MTC ) in phase I. PATIENTS AND METHODS We conducted a double-blind , phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC . Patients were r and omly assigned ( 2:1 ) to cabozantinib ( 140 mg per day ) or placebo . The primary end point was progression-free survival ( PFS ) . Additional outcome measures included tumor response rate , overall survival , and safety . RESULTS The estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo ( hazard ratio , 0.28 ; 95 % CI , 0.19 to 0.40 ; P < .001 ) . Prolonged PFS with cabozantinib was observed across all subgroups including by age , prior TKI treatment , and RET mutation status ( hereditary or sporadic ) . Response rate was 28 % for cabozantinib and 0 % for placebo ; responses were seen regardless of RET mutation status . Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3 % for cabozantinib and 7.2 % for placebo . Common cabozantinib-associated adverse events included diarrhea , palmar-plantar erythrodysesthesia , decreased weight and appetite , nausea , and fatigue and result ed in dose reductions in 79 % and holds in 65 % of patients . Adverse events led to treatment discontinuation in 16 % of cabozantinib-treated patients and in 8 % of placebo-treated patients . CONCLUSION Cabozantinib ( 140 mg per day ) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease . This dose of cabozantinib was associated with significant but manageable toxicity OBJECTIVE We conducted a prospect i ve 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 h and foot syndrome , weight loss , diarrhea , and rash . CONCLUSION Sorafenib has clinical ly relevant antitumor activity in patients with progressive metastatic or locally advanced radio-iodine refractory differentiated thyroid cancer .  Sorafenib can nowadays be considered as the st and ard option in these patients PURPOSE Ras/Raf/MAPK kinase/ERK and rearranged in transformation ( RET ) kinase pathways are important in thyroid cancer . We tested sorafenib , a B-Raf , RET , and vascular endothelial growth factor receptor kinase inhibitor , combined with tipifarnib , a farnesyltransferase inhibitor that inactivates Ras and other farnesylated proteins . PATIENTS AND METHODS We treated 35 patients with differentiated thyroid cancer ( DTC ) and medullary thyroid cancer ( MTC ) in a phase I trial . Sorafenib and tipifarnib were given for 21 d with 7 d rest in each 28-d cycle . RESULTS We enrolled 22 patients with metastatic DTC ( 16 papillary , five follicular , and one poorly differentiated ) and 13 patients with MTC , of whom 15 with DTC and 10 with MTC reached first restaging . When tissue was available , eight of 15 DTC patients ( 53 % ) had B-Raf mutations ; eight of 13 MTC ( 61.5 % ) patients had RET mutations . MTC partial response rate was 38 % ( five of 13 ) ( duration = 9 + , 12 , 13 , 16 + , and 34 + months ) , stable disease of at least 6 months was 31 % ( four of 13 ) . The DTC partial response rate was 4.5 % ( one of 22 ) , and stable disease of at least 6 months was 36 % ( eight of 22 ) . Median progression-free survival for all 35 patients was 18 months ( 95 % confidence interval , 14.6 to not reached months ) . Median overall survival has not been reached , with a median follow-up of 24 months with 80 % overall survival . Grade 1 - 2 toxicities were mainly rash , fatigue , and diarrhea . The most common grade 3 - 4 toxicities were rash , rise in amylase/lipase , and fatigue . CONCLUSIONS Inhibiting the Ras/Raf/MAPK kinase/ERK and RET kinase pathways with sorafenib and tipifarnib is well tolerated and active against thyroid cancer 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 
    Output:
    