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: BACKGROUND Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers . We assessed this agent 's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline . METHODS In this r and omised , double-blind , phase 2 trial undertaken in France and Austria , we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment . These patients were r and omly assigned ( 1:1 ) into one of the following four cohorts : liposarcoma , leiomyosarcoma , synovial sarcoma , and other sarcomas . Participants were treated with oral regorafenib ( 160 mg per day 3 weeks on and 1 week off ) or matched placebo . Patients receiving placebo were offered optional crossover in case of central ly confirmed disease progression . The r and om allocation schedule was computer-generated with permuted blocks of four patients , with two stratification factors : country ( France or Austria ) and previous exposure to pazopanib ( yes or no ) . Eligibility criteria included patients with histologically proven advanced and inoperable soft tissue sarcomas with intolerance or failure to doxorubicin or other anthracycline-based chemotherapy and at least one unidimensionally or bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors ( RECIST ; version 1.1 ) . The primary endpoint was RECIST-based progression-free survival after central radiological review in the intention-to-treat population . Patients , physicians , and radiologists of the panel were masked to treatment allocation . This study is still open for recruitment for an additional stratum ( patients previously treated with pazopanib ) and registered with Clinical Trials.gov , NCT01900743 . FINDINGS From Aug 5 , 2013 , to Nov 26 , 2014 , 182 patients were r and omly assigned to one of four cohorts and included in the final analysis . At the cutoff date ( Jan 7 , 2016 ) , the number of required events was reached for the four cohorts . In the liposarcoma cohort , progression-free survival was 1·1 months ( 95 % CI 0·9 - 2·3 ) with regorafenib versus 1·7 months ( 0·9 - 1·8 ) with placebo ( HR 0·89 [ 95 % CI 0·48 - 1·64 ] p=0·70 ) . In the leiomyosarcoma cohort , progression-free survival was 3·7 months ( 95 % CI 2·5 - 5·0 ) with regorafenib versus 1·8 ( 1·0 - 2·8 ) months with placebo ( HR 0·46 [ 95 % CI 0·46 - 0·80 ] p=0·0045 ) . In the synovial sarcoma cohort , progression-free survival was 5·6 months ( 95 % CI 1·4 - 11·6 ) with regorafenib versus 1·0 ( 0·8 - 1·4 ) with placebo ( HR 0·10 [ 95 % CI 0·03 - 0·35 ] p<0·0001 ) . In the other sarcoma cohort , progression-free survival was 2·9 months ( 95 % CI 1·0 - 7·8 ) with regorafenib versus 1·0 ( 0·9 - 1·9 ) with placebo ( HR 0·46 [ 95 % CI 0·25 - 0·81 ] p=0·0061 ) . Before crossover , the most common clinical ly significant grade 3 or higher adverse events were arterial hypertension ( 17 [ 19 % ] events in the 89 patients in the regorafenib group vs two [ 2 % ] events in the 92 patients in the placebo group ) , h and and foot skin reaction ( 14 [ 15 % ] vs no events ) and asthenia ( 12 [ 13 % ] vs six [ 6 % ] ) . One treatment-related death occurred in the regorafenib group due to liver failure . INTERPRETATION Regorafenib has an important clinical antitumour effect in non-adipocytic soft tissue sarcomas , improving progression-free survival . Regorafenib should be further evaluated in this setting , and its therapeutic role has to be defined in the context of the growing therapeutic armamentarium , already including one approved multikinase inhibitor , pazopanib . FUNDING Bayer HealthCare BACKGROUND The EORTC-STBSG coordinated two large trials of adjuvant chemotherapy ( CT ) in localized high- grade soft tissue sarcoma ( STS ) . Both studies failed to demonstrate any benefit on overall survival ( OS ) . The aim of the analysis of these two trials was to identify subgroups of patients who may benefit from adjuvant CT .  PATIENTS AND METHODS Individual patient data from two EORTC trials comparing doxorubicin-based CT to observation only in completely resected STS ( large resection , R0/marginal resection , R1 ) were pooled . Prognostic factors were assessed by univariate and multivariate analyses . Patient outcomes were subsequently compared between the two groups of patients according to each analyzed factor . RESULTS A total of 819 patients had been enrolled with a median follow-up of 8.2 years .  Tumor size , high histological grade and R1 resection emerged as independent adverse prognostic factors for relapse-free survival ( RFS ) and OS .  Adjuvant CT is an independent favorable prognostic factor for RFS but not for OS . A significant interaction between benefit of adjuvant CT and age , gender and R1 resection was observed for RFS and OS .  Males and patients > 40 years had a significantly better RFS in the treatment arms , while adjuvant CT was associated with a marginally worse OS in females and patients < 40 years . Patients with R1 resection had a significantly better RFS and OS favoring adjuvant CT arms . CONCLUSION Adjuvant CT is not associated with a better OS in young patients or in any pathology subgroup . Poor quality of initial surgery is the most important prognostic and predictive factor for utility of adjuvant CT in STS . Based on these data , we conclude that adjuvant CT for STS remains an investigational procedure and is not a routine st and ard of care BACKGROUND A non-r and omised , phase 2 study showed activity and tolerability of eribulin in advanced or metastatic soft-tissue sarcoma . In this phase 3 study , we aim ed to compare overall survival in patients with advanced or metastatic soft-tissue sarcoma who received eribulin with that in patients who received dacarbazine  ( an active control ) . METHODS We did this r and omised , open-label , phase 3 study across 110 study sites in 22 countries . We enrolled patients aged 18 years or older with intermediate- grade or high- grade advanced liposarcoma or leiomyosarcoma who had received at least two previous systemic regimens for advanced disease ( including an anthracycline ) . Using an interactive voice and web response system , an independent statistician r and omly assigned ( 1:1 ) patients to receive eribulin mesilate ( 1·4 mg/m(2 ) intravenously on days 1 and 8) or dacarbazine ( 850 mg/m(2 ) , 1000 mg/m(2 ) , or 1200 mg/m(2 ) [ dose dependent on centre and clinician ] intravenously on day 1 ) every 21 days until disease progression . R and omisation was stratified by disease type , geographical region , and number of previous regimens for advanced soft-tissue sarcoma and in blocks of six . Patients and investigators were not masked to treatment assignment . The primary endpoint was overall survival in the intention-to-treat population . The study is registered with Clinical Trials.gov , number NCT01327885 , and is closed to recruitment , but treatment and follow-up continue . FINDINGS Between March 10 , 2011 and May 22 , 2013 , we r and omly assigned patients to eribulin ( n=228 ) or dacarbazine ( n=224 ) . Overall survival was significantly improved in patients assigned to eribulin compared with those assigned to dacarbazine ( median 13·5 months [ 95 % CI 10·9 - 15·6 ] vs 11·5 months [ 9·6 - 13·0 ] ; hazard ratio 0·77 [ 95 % CI 0·62 - 0·95 ] ; p=0·0169 ) . Treatment-emergent adverse events occurred in 224 ( 99 % ) of 226 patients who received eribulin and 218 ( 97 % ) of 224 who received dacarbazine  . Grade 3 or higher adverse events were more common in patients who received eribulin ( 152 [ 67 % ] ) than in those who received dacarbazine ( 126 [ 56 % ] ) , as were deaths ( 10 [ 4 % ] vs 3 [ 1 % ] ) ; one death ( in the eribulin group ) was considered treatment-related by the investigators . INTERPRETATION Overall survival was improved in patients assigned to eribulin compared with those assigned to an active control , suggesting that eribulin could be a treatment option for advanced soft-tissue sarcoma . FUNDING Eisai Single‐agent gemcitabine and vinorelbine have activity in treatment of patients with soft‐tissue sarcomas . The combination of gemcitabine plus vinorelbine has activity against several forms of metastatic carcinoma with acceptable toxicity . This study evaluated the efficacy and tolerability of gemcitabine plus vinorelbine in advanced soft‐tissue sarcoma In this phase II study the effect of high-dose ifosfamide ( HDI ) given as a 3-day continuous infusion at a dose of 12 g/m2 repeated every 4 weeks with adequate mesna protection and hydration was evaluated in patients with advanced soft tissue sarcomas . A total of 124 patients entered the trial of which 10 were ineligible .  HDI was given both as first-line and second-line chemotherapy .  Median age was 46 years ( 19 - 66 years ) . Median World Health Organization ( WHO ) performance status was 1 ( 0 - 1 ) . Fifty two per cent of the patients were males . The predominant histology was leiomyosarcoma ( 33 % ) . A maximum of six cycles was given . At the time of analysis 55 patients have died . The partial response ( PR ) rate was 16 % . The median time to progression was 15 weeks . 8 of the 18 responding patients ( 44 % ) had synovial sarcomas , whereas only 5 % of the patients having leiomyosarcomas responded . The grade 3 + 4 haematological toxicity encountered was neutrophils in 78 % and platelets in 12 % . The major grade 3 + 4 non-haematological toxicities encountered were febrile neutropenia in 39 % , infection in 20 % , and acute renal failure in 4 % . In conclusion , it is possible to administer HDI on a multicentre basis , but the toxicity is substantial . HDI given as a continuous infusion at this dose can not be recommended as the st and ard treatment of advanced soft tissue sarcomas , even in selected patients BACKGROUND Eribulin inhibits microtubule dynamics via a mechanism distinct from that of other tubulin-targeting drugs , inducing cell-cycle arrest and tumour regression in pre clinical models . We assessed the activity and safety of eribulin in four strata of patients with different types of soft-tissue sarcoma . METHODS In this non-r and omised multicentre phase 2 study , patients were included if they had progressive or high- grade soft-tissue sarcoma and had received no more than one previous combination chemotherapy or up to two single drugs for advanced disease . They were stratified by the type of soft-tissue sarcoma they had . Eribulin was given intravenously at a concentration of 1·4 mg/m(2 ) over 2 - 5 min at days 1 and 8 every 3 weeks to primarily assess progression-free survival at 12 weeks ( RECIST 1.0 ) , which we evaluated in all patients who started treatment . Safety analyses were done in all patients who started treatment . This trial is registered at Clinical Trials.gov , number NCT00413192 . FINDINGS Of 128 patients included , 37 had adipocytic sarcoma , 40 had leiomyosarcoma , 19 had synovial sarcoma , and 32 had other sarcomas . 12 ( 31·6 % ) of 38 patients with leiomyosarcoma evaluable for the primary endpoint , 15 ( 46·9 % ) of 32 patients with adipocytic sarcoma , four ( 21·1 % ) of 19 with synovial sarcoma , and five ( 19·2 % ) of 26 in other sarcomas were progression-free at 12 weeks . The most common grade 3 - 4 adverse events were neutropenia ( 66 [ 52 % ] of 127 patients evaluable for safety ) , leucopenia ( 44 [ 35 % ] ) , anaemia ( nine [ 7 % ] ) , fatigue ( nine [ 7 % ] 
    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: BACKGROUND Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers . We assessed this agent 's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline . METHODS In this r and omised , double-blind , phase 2 trial undertaken in France and Austria , we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment . These patients were r and omly assigned ( 1:1 ) into one of the following four cohorts : liposarcoma , leiomyosarcoma , synovial sarcoma , and other sarcomas . Participants were treated with oral regorafenib ( 160 mg per day 3 weeks on and 1 week off ) or matched placebo . Patients receiving placebo were offered optional crossover in case of central ly confirmed disease progression . The r and om allocation schedule was computer-generated with permuted blocks of four patients , with two stratification factors : country ( France or Austria ) and previous exposure to pazopanib ( yes or no ) . Eligibility criteria included patients with histologically proven advanced and inoperable soft tissue sarcomas with intolerance or failure to doxorubicin or other anthracycline-based chemotherapy and at least one unidimensionally or bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors ( RECIST ; version 1.1 ) . The primary endpoint was RECIST-based progression-free survival after central radiological review in the intention-to-treat population . Patients , physicians , and radiologists of the panel were masked to treatment allocation . This study is still open for recruitment for an additional stratum ( patients previously treated with pazopanib ) and registered with Clinical Trials.gov , NCT01900743 . FINDINGS From Aug 5 , 2013 , to Nov 26 , 2014 , 182 patients were r and omly assigned to one of four cohorts and included in the final analysis . At the cutoff date ( Jan 7 , 2016 ) , the number of required events was reached for the four cohorts . In the liposarcoma cohort , progression-free survival was 1·1 months ( 95 % CI 0·9 - 2·3 ) with regorafenib versus 1·7 months ( 0·9 - 1·8 ) with placebo ( HR 0·89 [ 95 % CI 0·48 - 1·64 ] p=0·70 ) . In the leiomyosarcoma cohort , progression-free survival was 3·7 months ( 95 % CI 2·5 - 5·0 ) with regorafenib versus 1·8 ( 1·0 - 2·8 ) months with placebo ( HR 0·46 [ 95 % CI 0·46 - 0·80 ] p=0·0045 ) . In the synovial sarcoma cohort , progression-free survival was 5·6 months ( 95 % CI 1·4 - 11·6 ) with regorafenib versus 1·0 ( 0·8 - 1·4 ) with placebo ( HR 0·10 [ 95 % CI 0·03 - 0·35 ] p<0·0001 ) . In the other sarcoma cohort , progression-free survival was 2·9 months ( 95 % CI 1·0 - 7·8 ) with regorafenib versus 1·0 ( 0·9 - 1·9 ) with placebo ( HR 0·46 [ 95 % CI 0·25 - 0·81 ] p=0·0061 ) . Before crossover , the most common clinical ly significant grade 3 or higher adverse events were arterial hypertension ( 17 [ 19 % ] events in the 89 patients in the regorafenib group vs two [ 2 % ] events in the 92 patients in the placebo group ) , h and and foot skin reaction ( 14 [ 15 % ] vs no events ) and asthenia ( 12 [ 13 % ] vs six [ 6 % ] ) . One treatment-related death occurred in the regorafenib group due to liver failure . INTERPRETATION Regorafenib has an important clinical antitumour effect in non-adipocytic soft tissue sarcomas , improving progression-free survival . Regorafenib should be further evaluated in this setting , and its therapeutic role has to be defined in the context of the growing therapeutic armamentarium , already including one approved multikinase inhibitor , pazopanib . FUNDING Bayer HealthCare BACKGROUND The EORTC-STBSG coordinated two large trials of adjuvant chemotherapy ( CT ) in localized high- grade soft tissue sarcoma ( STS ) . Both studies failed to demonstrate any benefit on overall survival ( OS ) . The aim of the analysis of these two trials was to identify subgroups of patients who may benefit from adjuvant CT .  PATIENTS AND METHODS Individual patient data from two EORTC trials comparing doxorubicin-based CT to observation only in completely resected STS ( large resection , R0/marginal resection , R1 ) were pooled . Prognostic factors were assessed by univariate and multivariate analyses . Patient outcomes were subsequently compared between the two groups of patients according to each analyzed factor . RESULTS A total of 819 patients had been enrolled with a median follow-up of 8.2 years .  Tumor size , high histological grade and R1 resection emerged as independent adverse prognostic factors for relapse-free survival ( RFS ) and OS .  Adjuvant CT is an independent favorable prognostic factor for RFS but not for OS . A significant interaction between benefit of adjuvant CT and age , gender and R1 resection was observed for RFS and OS .  Males and patients > 40 years had a significantly better RFS in the treatment arms , while adjuvant CT was associated with a marginally worse OS in females and patients < 40 years . Patients with R1 resection had a significantly better RFS and OS favoring adjuvant CT arms . CONCLUSION Adjuvant CT is not associated with a better OS in young patients or in any pathology subgroup . Poor quality of initial surgery is the most important prognostic and predictive factor for utility of adjuvant CT in STS . Based on these data , we conclude that adjuvant CT for STS remains an investigational procedure and is not a routine st and ard of care BACKGROUND A non-r and omised , phase 2 study showed activity and tolerability of eribulin in advanced or metastatic soft-tissue sarcoma . In this phase 3 study , we aim ed to compare overall survival in patients with advanced or metastatic soft-tissue sarcoma who received eribulin with that in patients who received dacarbazine  ( an active control ) . METHODS We did this r and omised , open-label , phase 3 study across 110 study sites in 22 countries . We enrolled patients aged 18 years or older with intermediate- grade or high- grade advanced liposarcoma or leiomyosarcoma who had received at least two previous systemic regimens for advanced disease ( including an anthracycline ) . Using an interactive voice and web response system , an independent statistician r and omly assigned ( 1:1 ) patients to receive eribulin mesilate ( 1·4 mg/m(2 ) intravenously on days 1 and 8) or dacarbazine ( 850 mg/m(2 ) , 1000 mg/m(2 ) , or 1200 mg/m(2 ) [ dose dependent on centre and clinician ] intravenously on day 1 ) every 21 days until disease progression . R and omisation was stratified by disease type , geographical region , and number of previous regimens for advanced soft-tissue sarcoma and in blocks of six . Patients and investigators were not masked to treatment assignment . The primary endpoint was overall survival in the intention-to-treat population . The study is registered with Clinical Trials.gov , number NCT01327885 , and is closed to recruitment , but treatment and follow-up continue . FINDINGS Between March 10 , 2011 and May 22 , 2013 , we r and omly assigned patients to eribulin ( n=228 ) or dacarbazine ( n=224 ) . Overall survival was significantly improved in patients assigned to eribulin compared with those assigned to dacarbazine ( median 13·5 months [ 95 % CI 10·9 - 15·6 ] vs 11·5 months [ 9·6 - 13·0 ] ; hazard ratio 0·77 [ 95 % CI 0·62 - 0·95 ] ; p=0·0169 ) . Treatment-emergent adverse events occurred in 224 ( 99 % ) of 226 patients who received eribulin and 218 ( 97 % ) of 224 who received dacarbazine  . Grade 3 or higher adverse events were more common in patients who received eribulin ( 152 [ 67 % ] ) than in those who received dacarbazine ( 126 [ 56 % ] ) , as were deaths ( 10 [ 4 % ] vs 3 [ 1 % ] ) ; one death ( in the eribulin group ) was considered treatment-related by the investigators . INTERPRETATION Overall survival was improved in patients assigned to eribulin compared with those assigned to an active control , suggesting that eribulin could be a treatment option for advanced soft-tissue sarcoma . FUNDING Eisai Single‐agent gemcitabine and vinorelbine have activity in treatment of patients with soft‐tissue sarcomas . The combination of gemcitabine plus vinorelbine has activity against several forms of metastatic carcinoma with acceptable toxicity . This study evaluated the efficacy and tolerability of gemcitabine plus vinorelbine in advanced soft‐tissue sarcoma In this phase II study the effect of high-dose ifosfamide ( HDI ) given as a 3-day continuous infusion at a dose of 12 g/m2 repeated every 4 weeks with adequate mesna protection and hydration was evaluated in patients with advanced soft tissue sarcomas . A total of 124 patients entered the trial of which 10 were ineligible .  HDI was given both as first-line and second-line chemotherapy .  Median age was 46 years ( 19 - 66 years ) . Median World Health Organization ( WHO ) performance status was 1 ( 0 - 1 ) . Fifty two per cent of the patients were males . The predominant histology was leiomyosarcoma ( 33 % ) . A maximum of six cycles was given . At the time of analysis 55 patients have died . The partial response ( PR ) rate was 16 % . The median time to progression was 15 weeks . 8 of the 18 responding patients ( 44 % ) had synovial sarcomas , whereas only 5 % of the patients having leiomyosarcomas responded . The grade 3 + 4 haematological toxicity encountered was neutrophils in 78 % and platelets in 12 % . The major grade 3 + 4 non-haematological toxicities encountered were febrile neutropenia in 39 % , infection in 20 % , and acute renal failure in 4 % . In conclusion , it is possible to administer HDI on a multicentre basis , but the toxicity is substantial . HDI given as a continuous infusion at this dose can not be recommended as the st and ard treatment of advanced soft tissue sarcomas , even in selected patients BACKGROUND Eribulin inhibits microtubule dynamics via a mechanism distinct from that of other tubulin-targeting drugs , inducing cell-cycle arrest and tumour regression in pre clinical models . We assessed the activity and safety of eribulin in four strata of patients with different types of soft-tissue sarcoma . METHODS In this non-r and omised multicentre phase 2 study , patients were included if they had progressive or high- grade soft-tissue sarcoma and had received no more than one previous combination chemotherapy or up to two single drugs for advanced disease . They were stratified by the type of soft-tissue sarcoma they had . Eribulin was given intravenously at a concentration of 1·4 mg/m(2 ) over 2 - 5 min at days 1 and 8 every 3 weeks to primarily assess progression-free survival at 12 weeks ( RECIST 1.0 ) , which we evaluated in all patients who started treatment . Safety analyses were done in all patients who started treatment . This trial is registered at Clinical Trials.gov , number NCT00413192 . FINDINGS Of 128 patients included , 37 had adipocytic sarcoma , 40 had leiomyosarcoma , 19 had synovial sarcoma , and 32 had other sarcomas . 12 ( 31·6 % ) of 38 patients with leiomyosarcoma evaluable for the primary endpoint , 15 ( 46·9 % ) of 32 patients with adipocytic sarcoma , four ( 21·1 % ) of 19 with synovial sarcoma , and five ( 19·2 % ) of 26 in other sarcomas were progression-free at 12 weeks . The most common grade 3 - 4 adverse events were neutropenia ( 66 [ 52 % ] of 127 patients evaluable for safety ) , leucopenia ( 44 [ 35 % ] ) , anaemia ( nine [ 7 % ] ) , fatigue ( nine [ 7 % ] 
    Output:
    