***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: The article presents final analyses of overall survival from a phase III trial of lapatinib and capecitabine in patients with human epidermal growth factor receptor 2–positive locally advanced or metastatic breast cancer that progressed following prior therapy including trastuzumab 1006 Background : The addition of bevacizumab ( Bev ) to EC-docetaxel chemotherapy ( CT ) did not improve pathological complete response ( pCR ) rates in unselected patients ( P ) with HER2 negative breast cancers ( von Minckwitz G et al , San Antonio 2010 ) . Secondary aim of GeparQuinto was to determine pCR rates in patients with triple-negative breast cancer ( TNBC ) exclusively . METHODS P with untreated TNBC ( ER and PgR < 10 % and HER2 IHC score 0/1 or FISH negative ; detected locally ) were included in GeparQuinto if they had T1c-T4d tumors and showed no increased cardiac or bleeding risks . P were r and omized to receive 4 cycles EC ( 90/600 mg/m² ) q3w followed by 4 cycles docetaxel ( 100mg/m² ) with or without Bev 15mg/kg q3w added to CT cycles . P not clinical ly responding to EC ± Bev were considered as treatment failures and entered another part of the protocol . P were a stratified subset of the 1948 participants of the HER2 negative part of GeparQuinto . RESULTS In total 684 P with TNBC were r and omized to EC-D ( N=345 ) and EC-D+Bev ( N=339 ) . Median tumor size was 35 / 35 [ -Bev / + Bev ] mm ( clinical ly ) and 28.5 / 28 mm ( sonographically ) ; 15.7 % / 16.0 % had T3 - 4a-d , 1.2 % / 1.5 % bilateral , 13.3 % / 12.7 % multifocal , and 5.8 % / 6.5 % multicentric disease , 97.1 % / 97.9 % had non-lobular , 71.6 % / 69.6 % grade 3 , 57.2 % / 58.0 % node-positive . 32.9 % / 28.7 % discontinued treatment , 20.7 % / 12.3 % due to no response after 4xEC . Additional 4.7 % continued CT but stopped Bev . pCR rate % ( ypT0 , ypN0 ; primary endpoint ) was 27.8 / 36.4 ( p=0.021 ) . Rate of P with ypT0/is was 36.5 / 44.6 ( p=0.04 ) and ypT0/is ypN0 was 32.7 / 40.1 ( p=0.059 ) . If pCRs in non-responding P were included , ypT0,ypN0 rates raised to 28.7 / 38.2 ; ypT0/is ypN0 rates to 33.9 % / 41.9 % . If only P with ER=0 % , PgR=0 % were considered , ypT0 ypN0 was 32.3 % / 40.1 % . Bev treatment ( p=0.013 ) , age ( p=0.021 ) , cT ( p=0.042 ) and grade ( p=0.004 ) were independent predictors for pCR in multivariate logistic regression analysis . Breast conservation was achieved in 75.2 % / 71.5 % ( p=0.39 ) . CONCLUSIONS The effect of Bev on pCR in the GeparQuinto study was restricted exclusively to patients with TNBC . Long term follow-up has to be awaited OBJECTIVE Our purpose was to measure the agreement , reliability , construct validity , and feasibility of a measurement tool to assess  systematic review s ( AMSTAR ) . STUDY DESIGN AND SETTING We r and omly selected 30 systematic review s from a data base . Each was assessed by two review ers using : ( 1 ) the enhanced quality assessment question naire ( Overview of Quality Assessment Question naire [ OQAQ ] ) ; ( 2 ) Sacks ' instrument ; and ( 3 ) our newly developed measurement tool ( AMSTAR ) . We report on reliability ( interobserver kappas of the 11 AMSTAR items ) , intraclass correlation coefficients ( ICCs ) of the sum scores , construct validity ( ICCs of the sum scores of AMSTAR compared with those of other instruments ) , and completion times . RESULTS The interrater agreement of the individual items of AMSTAR was substantial with a mean kappa of 0.70 ( 95 % confidence interval [ CI ] : 0.57 , 0.83 ) ( range : 0.38 - 1.0 ) . Kappas recorded for the other instruments were 0.63 ( 95 % CI : 0.38 , 0.78 ) for enhanced OQAQ and 0.40 ( 95 % CI : 0.29 , 0.50 ) for the Sacks ' instrument . The ICC of the total score for AMSTAR was 0.84 ( 95 % CI : 0.65 , 0.92 ) compared with 0.91 ( 95 % CI : 0.82 , 0.96 ) for OQAQ and 0.86 ( 95 % CI : 0.71 , 0.94 ) for the Sacks ' instrument . AMSTAR proved easy to apply , each review taking about 15 minutes to complete . CONCLUSIONS AMSTAR has good agreement , reliability , construct validity , and feasibility . These findings need confirmation by a broader range of assessors and a more diverse range of review Background : Information on major harms of medical interventions comes primarily from epidemiologic studies performed after licensing and marketing . Comparison with data from large-scale r and omized trials is occasionally feasible . We compared evidence from r and omized trials with that from epidemiologic studies to determine whether they give different estimates of risk for important harms of medical interventions . Methods : We targeted well-defined , specific harms of various medical interventions for which data were already available from large-scale r and omized trials ( > 4000 subjects ) . Nonr and omized studies involving at least 4000 subjects addressing these same harms were retrieved through a search of MEDLINE . We compared the relative risks and absolute risk differences for specific harms in the r and omized and nonr and omized studies . Results : Eligible nonr and omized studies were found for 15 harms for which data were available from r and omized trials addressing the same harms . Comparisons of relative risks between the study types were feasible for 13 of the 15 topics , and of absolute risk differences for 8 topics . The estimated increase in relative risk differed more than 2-fold between the r and omized and nonr and omized studies for 7 ( 54 % ) of the 13 topics ; the estimated increase in absolute risk differed more than 2-fold for 5 ( 62 % ) of the 8 topics . There was no clear predilection for r and omized or nonr and omized studies to estimate greater relative risks , but usually ( 75 % [ 6/8 ] ) the r and omized trials estimated larger absolute excess risks of harm than the nonr and omized studies did . Interpretation : Nonr and omized studies are often conservative in estimating absolute risks of harms . It would be useful to compare and scrutinize the evidence on harms obtained from both r and omized and nonr and omized studies Purpose : Taxanes have effects on angiogenesis causing difficulties in separating biological effects of chemotherapy from those due to angiogenesis inhibitors . This r and omized phase II trial was design ed to evaluate the additional biomarker effect on angiogenesis when bevacizumab is added to docetaxel . Experimental Design : Patients with inoperable breast cancer were r and omized to either 2 cycles of preoperative docetaxel ( D ) 35 mg/m2 i.v . weekly for 6 weeks , followed by a 2-week break ; or docetaxel with bevacizumab 10 mg/kg i.v . every other week for a total of 16 weeks ( DB ) . Plasma and serum markers of endothelial damage , dynamic contrast-enhanced magnetic resonance imaging ( DCE-MRI ) , and tumor microvessel density were assessed before treatment and at the end of each preoperative cycle . Results : Forty-nine patients were r and omized ( DB , 24 ; D , 25 ) . There was no difference in overall clinical response , progression-free survival , or overall survival . Vascular endothelial growth factor increased during treatment ; more so with DB ( P < 0.0001 ) . Vascular cell adhesion molecule-1 ( VCAM-1 ) also increased ( P < 0.0001 ) ; more so with DB ( P = 0.069 ) . Intercellular adhesion molecule increased ( P = 0.018 ) and E-selectin decreased ( P = 0.006 ) overall . Baseline levels of VCAM-1 and E-selectin correlated with clinical response by univariate analysis . DCE-MRI showed a greater decrease in tumor perfusion calculated by initial area under the curve for the first 90 seconds in DB ( P = 0.024 ) . DCE-MRI also showed an overall decrease in tumor volume ( P = 0.012 ) . Conclusion : Bevacizumab plus docetaxel caused a greater increase in vascular endothelial growth factor and VCAM-1 , and a greater reduction in tumor perfusion by DCE-MRI compared with docetaxel . Clinical outcomes of inoperable breast cancer were predicted by changes in VCAM-1 and E-selectin This multicenter , r and omized , open-label phase III trial ( planned enrollment : 700 patients ) was conducted to test the hypothesis that single-agent sunitinib improves progression-free survival ( PFS ) compared with capecitabine as treatment for advanced breast cancer ( ABC ) . Patients with HER2-negative ABC that recurred after anthracycline and taxane therapy  were r and omized ( 1:1 ) to sunitinib 37.5 mg/day or capecitabine 1,250 mg/m2 ( 1,000 mg/m2 in patients > 65 years ) BID on days 1–14 q3w . The independent data -monitoring committee ( DMC ) determined during the first interim analysis ( 238 patients r and omized to sunitinib , 244 to capecitabine ) that the trial be terminated due to futility in reaching the primary endpoint . No statistical evidence supported the hypothesis that sunitinib improved PFS compared with capecitabine ( one-sided P = 0.999 ) . The data indicated that PFS was shorter with sunitinib than capecitabine ( median 2.8 vs. 4.2 months , respectively ; HR , 1.47 ; 95 % CI , 1.16–1.87 ; two-sided P = 0.002 ) . Median overall survival ( 15.3 vs. 24.6 months ; HR , 1.17 ; two-sided P = 0.350 ) and objective response rates ( 11 vs. 16 % ; odds ratio , 0.65 ; P = 0.109 ) were numerically inferior with sunitinib versus capecitabine . While no new or unexpected safety findings were reported , sunitinib treatment was associated with higher frequencies and greater severities of many common adverse events ( AEs ) compared with capecitabine , result ing in more temporary discontinuations due to AEs with sunitinib ( 66 vs. 51 % ) . The relative dose intensity was lower with sunitinib than capecitabine ( 73 vs. 95 % ) . Based on these efficacy and safety results , sunitinib should not be used as monotherapy for patients with ABC This is the last in a series of four articles Prognostic studies include clinical studies of variables predictive of future events as well as epidemiological studies of aetiological risk factors . As multiple similar studies accumulate it becomes increasingly important to identify and evaluate all of the relevant studies to develop a more reliable overall assessment . For prognostic studies this is not straightforward . Box 1 summarises the clinical importance of information on prognostic factors . Many of the issues discussed are also relevant to aetiological studies , especially cohort ones . Some features of prognostic studies lead to particular difficulties for the systematic review er . Firstly , in most clinical prognostic studies the outcome of primary interest is the time to an event , often death . Meta- analysis of such studies is rather more difficult than that for binary data or continuous measurements . Secondly , in many context s the prognostic variable of interest is often one of several prognostic variables . When examining a variable of interest research ers should consider other prognostic variables with which it might be correlated . Thirdly , many prognostic factors are continuous variables , for which research ers use a wide variety of methods of analysis . # # # # Summary points Systematic review s are applicable to all types of research design , and studies of prognostic variables are an important additional area where appropriate methodology should be applied Prognostic variables should be evaluated in a representative sample of patients assembled at a common point in the course of their disease — ideally they should all have received the same medical treatment or been in a r and omised trial When examined critically , a high proportion of prognostic studies are found to be method ologically poor Meta- analysis of published data is hampered by difficulties in extraction of data and variation in the characteristics of the study and patients The poor quality of the published literature is a strong argument in favour BACKGROUND Whether progression-free survival ( PFS ) or overall survival ( OS ) 
    Output:
    
PFS ( HR 0.67 ; 95 % confidence interval ( CI ) 0.61 to 0.73 ) and response rate were significantly better for patients treated with bevacizumab , with moderate heterogeneity regarding the magnitude of the effect on PFS .
Subgroup analysis stated a significant greater benefit for patients with previous ( taxane ) chemotherapy and patients with hormone-receptor negative status .
The overall patient benefit from adding bevacizumab to first- and second-line chemotherapy in metastatic breast cancer can at best be considered as modest .
It is dependent on the type of chemotherapy used and limited to a prolongation of PFS and response rates in both first- and second-line therapy , both surrogate parameters .
In contrast , bevacizumab has no significant impact on the patient-related secondary outcomes of OS or QoL , which indicate a direct patient benefit .