***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: PURPOSE To investigate whether sunitinib plus docetaxel improves clinical outcomes for patients with human epidermal growth factor receptor 2 (HER2)/neu-negative advanced breast cancer ( ABC ) versus docetaxel alone . PATIENTS AND METHODS In this phase III study , patients were r and omly assigned to open-label combination therapy ( sunitinib 37.5 mg/d , days 2 to 15 every 3 weeks ; and docetaxel 75 mg/m(2 ) , day 1 every 3 weeks ) or monotherapy ( docetaxel 100 mg/m(2 ) every 3 weeks ) .  Progression-free survival ( PFS )  was the primary end point . RESULTS Two hundred ninety-six patients were r and omly assigned to combination therapy , and 297 patients were assigned to monotherapy .  Median PFS times were 8.6 and 8.3 months with combination therapy and monotherapy , respectively ( hazard ratio , 0.92 ; one-sided P = .265 ) . The objective response rate ( ORR ) was significantly higher with the combination ( 55 % ) than with monotherapy ( 42 % ; one-sided P = .001 ) . Duration of response was similar in both arms ( 7.5 months with the combination v 7.2 months with monotherapy ) . Median overall survival ( OS ) times were 24.8 and 25.5 months with combination therapy and monotherapy , respectively ( one-sided P = .904 ) . There were 107 deaths with the combination and 91 deaths with monotherapy . The frequency of common adverse events ( AEs ) was higher with the combination , as were treatment discontinuations caused by AEs . CONCLUSION The combination of sunitinib plus docetaxel improved ORR but did not prolong either PFS or OS compared with docetaxel alone when given to an unselected HER2/neu-negative cohort as first-line treatment for ABC . Sunitinib combination therapy may also have result ed in AEs that yield an unfavorable risk-benefit ratio . The sunitinib-docetaxel regimen evaluated in this study is not recommended for further use in ABC PURPOSE This r and omized , open-label phase II study compared the efficacy of sunitinib monotherapy with that of single-agent st and ard-of-care ( SOC ) chemotherapy in patients with previously treated advanced triple-negative breast cancer ( TNBC ) . METHODS Patients with advanced TNBC , relapsed after anthracycline- and taxane-based chemotherapy  , were r and omized to receive either sunitinib ( 37.5 mg/day ) or the investigator 's choice of SOC therapy .  Progression-free survival was the primary endpoint . RESULTS Median progression-free survival was 2.0 months with sunitinib and 2.7 months with SOC chemotherapy ( one-sided P = 0.888 ) . Median overall survival was not prolonged with sunitinib ( 9.4 months ) compared with SOC chemotherapy ( 10.5 months ; one-sided P = 0.839 ) . The objective response rate was 3 % with sunitinib and 7 % with SOC chemotherapy ( one-sided P = 0.962 ) . CONCLUSIONS Sunitinib monotherapy did not improve efficacy compared with SOC chemotherapy in patients with previously treated advanced TNBC , for which identification of effective treatments and therapeutic targets remains an urgent need . TRIAL REGISTRATION NCT00246571 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 BACKGROUND Cediranib is a highly potent vascular endothelial growth factor ( VEGF ) signalling inhibitor with activity against VEGF receptors 1 , 2 and 3 . This Phase II , r and omised , double-blind , parallel-group study compared the efficacy of cediranib with placebo in patients with metastatic or recurrent clear cell renal cell carcinoma who had not previously received a VEGF signalling inhibitor . METHODS Patients were r and omised ( 3:1 ) to cediranib 45 mg/day or placebo .  The primary objective was comparison of change from baseline in tumour size after 12 weeks of therapy . Secondary objectives included response rate and duration , progression-free survival ( PFS ) and safety and tolerability . Patients in the placebo group could cross over to open-label cediranib at 12 weeks or earlier if their disease had progressed . This study has been completed and is registered with Clinical Trials.gov , number NCT00423332 . FINDINGS Patients ( n=71 ) were r and omised to receive cediranib ( n=53 ) or placebo ( n=18 ) . The primary study outcome revealed that , after 12weeks of therapy , there was a significant difference in mean percentage change from baseline in tumour size between the cediranib ( -20 % ) and placebo ( + 20 % ) arms ( p<0.0001 ) . Eighteen patients ( 34 % ) on cediranib achieved a partial response and 25 ( 47 % ) experienced stable disease .  Cediranib treatment prolonged PFS significantly compared with placebo ( hazard ratio (HR)=0.45 , 90%confidence interval : 0.26 - 0.76 , p=0.017 ; median PFS 12.1 versus 2.8 months ) . The most common adverse events in patients receiving cediranib were diarrhoea ( 74 % ) , hypertension ( 64 % ) , fatigue ( 58 % ) and dysphonia ( 58 % ) . INTERPRETATION Cediranib monotherapy demonstrated significant evidence of antitumour activity in patients with advanced renal cell carcinoma . The adverse event profile was consistent with previous studies of cediranib 45 mg This phase II study ( VEG20007 ; NCT00347919 ) with r and omized and open-label components evaluated first-line lapatinib plus pazopanib therapy and /or lapatinib monotherapy in patients with human epidermal growth factor receptor type 2 (HER2)-positive advanced/metastatic breast cancer . Patients were enrolled sequentially into two cohorts : Cohort 1 , patients were r and omly assigned to lapatinib 1,000 mg plus pazopanib 400 mg or lapatinib 1,500 mg monotherapy ; Cohort 2 , patients received lapatinib 1,500 mg plus pazopanib 800 mg . The primary endpoint was week-12 progressive disease rate ( PDR ) for Cohort 1 . The principal secondary endpoint was week-12 response rate ( RR ) for Cohort 2 . Efficacy was assessed in patients with central ly confirmed HER2 positivity ( modified intent-to-treat population [ MITT ] ) . The study enrolled 190 patients ( Cohort 1 , combination n = 77 , lapatinib n = 73 ; Cohort 2 , n = 40 ) . The MITT population comprised n = 141 ( Cohort 1 ) and n = 36 ( Cohort 2 ) . In Cohort 1 , week-12 PDRs were 36.2 % ( combination ) versus 38.9 % ( lapatinib ; P = 0.37 for the difference ) . Week-12 RRs were 36.2 % ( combination ) versus 22.2 % ( lapatinib ) . In Cohort 2 , week-12 RR was 33.3 % . In Cohort 1 , grade 3/4 adverse events ( AEs ) included diarrhea ( combination , 9 % ; lapatinib , 5 % ) and hypertension ( combination , 5 % ; lapatinib , 0 % ) . Grade s 3/4 AEs in Cohort 2 included diarrhea ( 40 % ) , hypertension ( 5 % ) , and fatigue ( 5 % ) . Alanine aminotransferase elevations > 5 times the upper limit of normal occurred in Cohort 1 ( combination , 18 % ; lapatinib , 5 % ) and Cohort 2 ( 20 % ) . Upon conclusion , the combination of lapatinib plus pazopanib did not improve PDR compared with lapatinib monotherapy , although RR was increased . Toxicity was higher with the combination , including increased diarrhea and liver enzyme elevations BACKGROUND Axitinib is a potent , selective inhibitor of vascular endothelial growth factor ( VEGF ) receptors 1 , 2 , and 3 . A r and omised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients . On the basis of these results , we aim ed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial . METHODS In this double-blind , placebo-controlled , phase 3 study , eligible patients had metastatic or locally advanced pancreatic adenocarcinoma , no uncontrolled hypertension or venous thrombosis , and Eastern Cooperative Oncology Group performance status 0 or 1 . Patients , stratified by disease extent ( metastatic vs locally advanced ) , were r and omly assigned ( 1:1 ) to receive gemcitabine 1000 mg/m(2 ) intravenously on days 1 , 8 , and 15 every 28 days plus either axitinib or placebo . Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day , which could be dose-titrated up to 10 mg twice daily if well tolerated . A central ised r and omisation procedure was used to assign patients to each treatment group , with r and omised permuted blocks within strata . Patients , investigators , and the trial sponsor were masked to treatment assignments . The primary endpoint was overall survival . All efficacy analyses were done in all patients assigned to treatment groups for whom data were available ; safety and treatment administration and compliance assessment s were based on treatment received . This study is registered at Clinical Trials.gov , number NCT00471146 . FINDINGS Between July 27 , 2007 , and Oct 31 , 2008 , 632 patients were enrolled and assigned to treatment groups  ( 316 axitinib , 316 placebo ) . At an interim analysis in January , 2009 , the independent data monitoring committee concluded that the futility boundary had been crossed . Median overall survival was 8·5 months ( 95 % CI 6·9 - 9·5 ) for gemcitabine plus axitinib ( n=314 , data missing for two patients ) and 8·3 months ( 6·9 - 10·3 ) for gemcitabine plus placebo ( n=316 ; hazard ratio 1·014 , 95 % CI 0·786 - 1·309 ; one-sided p=0·5436 ) . The most common grade 3 or higher adverse events  for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension ( 20 [ 7 % ] and 5 [ 2 % ] events , respectively ) , abdominal pain ( 20 [ 7 % ] and 17 [ 6 % ] ) , fatigue ( 27 [ 9 % ] and 21 [ 7 % ] ) , and anorexia ( 19 [ 6 % ] and 11 [ 4 % ] ) . INTERPRETATION The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer . These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease . FUNDING Pfizer This multi-center Phase II study evaluated lapatinib , pazopanib , and the combination in patients with relaps 
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Meta-regression indicated that CHF might possibly occur early in the treatment of VEGFR-TKIs .
The use of VEGFR-TKIs is associated with a significantly increased risk of developing congestive heart failure in cancer patients .