***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 evaluate single-agent activity of bevacizumab in patients with recurrent glioblastoma . PATIENTS AND METHODS Patients with recurrent glioblastoma were treated with bevacizumab 10 mg/kg every 2 weeks . After tumor progression , patients were immediately treated with bevacizumab in combination with irinotecan 340 mg/m(2 ) or 125 mg/m(2 ) every 2 weeks , depending on use of enzyme-inducing antiepileptic drugs . Complete patient evaluations were repeated every 4 weeks . RESULTS Forty-eight heavily pretreated patients were accrued to this study .  Thromboembolic events ( 12.5 % ) , hypertension ( 12.5 % ) , hypophosphatemia ( 6 % ) , and thrombocytopenia ( 6 % ) were the most common drug-associated adverse events . Six patients ( 12.5 % ) were removed from study for drug-associated toxicity ( five thromboembolic events , one bowel perforation ) . Thirty-four patients ( 71 % ) and 17 patients ( 35 % ) achieved radiographic response based on Levin and Macdonald criteria , respectively . Median progression-free survival ( PFS ) was 16 weeks ( 95 % CI , 12 to 26 weeks ) . The 6-month PFS was 29 % ( 95 % CI , 18 % to 48 % ) . The 6-month overall survival was 57 % ( 95 % CI , 44 % to 75 % ) . Median overall survival was 31 weeks ( 95 % CI , 21 to 54 weeks ) . Early magnetic resonance imaging response ( first 96 hours and 4 weeks ) was predictive of long-term PFS , with the Levin criteria being more predictive than Macdonald criteria . Of 19 patients treated with bevacizumab plus irinotecan at progression , there were no objective radiographic responses . Eighteen patients ( 95 % ) experienced disease progression by the second cycle , and the median PFS was 30 days . CONCLUSION We conclude that single-agent bevacizumab has significant biologic and antiglioma activity in patients with recurrent glioblastoma BACKGROUND Concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the st and ard of care for patients with newly diagnosed glioblastoma .  Bevacizumab , a humanized monoclonal antibody against vascular endothelial growth factor A , is currently approved for recurrent glioblastoma . Whether the addition of bevacizumab would improve survival among patients with newly diagnosed glioblastoma is not known . METHODS In this r and omized , double-blind , placebo-controlled trial , we treated adults who had central ly confirmed glioblastoma with radiotherapy ( 60 Gy ) and daily temozolomide .  Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy . At disease progression , the assigned treatment was revealed , and bevacizumab therapy could be initiated or continued . The trial was design ed to detect a 25 % reduction in the risk of death and a 30 % reduction in the risk of progression or death , the two co primary end points , with the addition of bevacizumab . RESULTS A total of 978 patients were registered , and 637 underwent r and omization . There was no significant difference in the duration of overall survival between the bevacizumab group and the placebo group ( median , 15.7 and 16.1 months , respectively ; hazard ratio for death in the bevacizumab group , 1.13 ) . Progression-free survival was longer in the bevacizumab group ( 10.7 months vs. 7.3 months ; hazard ratio for progression or death , 0.79 ) . There were modest increases in rates of hypertension , thromboembolic events , intestinal perforation , and neutropenia in the bevacizumab group . Over time , an increased symptom burden , a worse quality of life , and a decline in neurocognitive function were more frequent in the bevacizumab group . CONCLUSIONS First-line use of bevacizumab did not improve overall survival in patients with newly diagnosed glioblastoma .  Progression-free survival was prolonged but did not reach the prespecified improvement target . ( Funded by the National Cancer Institute ; Clinical Trials.gov number , NCT00884741 . ) 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 PURPOSE We evaluated the efficacy of bevacizumab , alone and in combination with irinotecan , in patients with recurrent glioblastoma in a phase II , multicenter , open-label , noncomparative trial . PATIENTS AND METHODS One hundred sixty-seven patients were r and omly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m(2 ) or 125 mg/m(2 ) ( with or without concomitant enzyme-inducing antiepileptic drugs , respectively ) once every 2 weeks . Primary end points were 6-month progression-free survival and objective response rate , as determined by independent radiology review . Secondary end points included safety and overall survival . RESULTS In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups , estimated 6-month progression-free survival rates were 42.6 % and 50.3 % , respectively ; objective response rates were 28.2 % and 37.8 % , respectively ; and median overall survival times were 9.2 months and 8.7 months , respectively . There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time . Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan , 46.4 % and 65.8 % , respectively , experienced grade > or = 3 adverse events , the most common of which were hypertension ( 8.3 % ) and convulsion ( 6.0 % ) in the bevacizumab-alone group and convulsion ( 13.9 % ) , neutropenia ( 8.9 % ) , and fatigue ( 8.9 % ) in the bevacizumab-plus-irinotecan group . Intracranial hemorrhage was noted in two patients ( 2.4 % ) in the bevacizumab-alone group ( grade 1 ) and in three patients ( 3.8 % ) patients in the bevacizumab-plus-irinotecan group ( grade s 1 , 2 , and 4 , respectively ) . CONCLUSION Bevacizumab , alone or in combination with irinotecan , was well tolerated and active in recurrent glioblastoma PURPOSE The European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada trial on temozolomide ( TMZ ) and radiotherapy ( RT ) in glioblastoma ( GBM ) has demonstrated that the combination of TMZ and RT conferred a significant and meaningful survival advantage compared with RT alone . We evaluated in this trial whether the recursive partitioning analysis ( RPA ) retains its overall prognostic value and what the benefit of the combined modality is in each RPA class . PATIENTS AND METHODS Five hundred seventy-three patients with newly diagnosed GBM were r and omly assigned to st and ard postoperative RT or to the same RT with concomitant TMZ followed by adjuvant TMZ . The primary end point was overall survival . The European Organisation for Research and Treatment of Cancer RPA used accounts for age , WHO performance status , extent of surgery , and the Mini-Mental Status Examination . RESULTS Overall survival was statistically different among RPA classes III , IV , and V , with median survival times of 17 , 15 , and 10 months , respectively , and 2-year survival rates of 32 % , 19 % , and 11 % , respectively ( P < .0001 ) . Survival with combined TMZ/RT  was higher in RPA class III , with 21 months median survival time and a 43 % 2-year survival rate , versus 15 months and 20 % for RT alone ( P = .006 ) . In RPA class IV , the survival advantage remained significant , with median survival times of 16 v 13 months , respectively , and 2-year survival rates of 28 % v 11 % , respectively ( P = .0001 ) . In RPA class V , however , the survival advantage of RT/TMZ was of borderline significance ( P = .054 ) . CONCLUSION RPA retains its prognostic significance overall as well as in patients receiving RT with or without TMZ for newly diagnosed GBM , particularly in classes III and IV BACKGROUND In 2004 , a r and omised phase III trial by the European Organisation for Research and Treatment of Cancer ( EORTC ) and National Cancer Institute of Canada Clinical Trials Group ( NCIC ) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy .  We report the final results with a median follow-up of more than 5 years . METHODS Adult patients with newly diagnosed glioblastoma were r and omly assigned to receive either st and ard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide . The methylation status of the methyl-guanine methyl transferase gene , MGMT , was determined retrospectively from the tumour tissue of 206 patients . The primary endpoint was overall survival . Analyses were by intention to treat . This trial is registered with Clinical trials.gov , number NCT00006353 . FINDINGS Between Aug 17 , 2000 , and March 22 , 2002 , 573 patients were assigned to treatment . 278 ( 97 % ) of 286 patients in the radiotherapy alone group and 254 ( 89 % ) of 287 in the combined-treatment group died during 5 years of follow-up . Overall survival was 27.2 % ( 95 % CI 22.2 - 32.5 ) at 2 years , 16.0 % ( 12.0 - 20.6 ) at 3 years , 12.1 % ( 8.5 - 16.4 ) at 4 years , and 9.8 % ( 6.4 - 14.0 ) at 5 years with temozolomide , versus 10.9 % ( 7.6 - 14.8 ) , 4.4 % ( 2.4 - 7.2 ) , 3.0 % ( 1.4 - 5.7 ) , and 1.9 % ( 0.6 - 4.4 ) with radiotherapy alone ( hazard ratio 0.6 , 95 % CI 0.5 - 0.7 ; p<0.0001 ) . A benefit of combined therapy was recorded in all clinical prognostic subgroups , including patients aged 60 - 70 years . Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy . INTERPRETATION Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up . A few patients in favourable prognostic categories survive longer than 5 years . MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide . FUNDING EORTC , NCIC , Nélia and Amadeo Barletta Foundation , Schering-Plough LBA2000 Background : In patients with MGMT-nonmethylated glioblastoma ( GBM ) , primary chemotherapy with temozolomide ( TMZ ) is at best moderately effective . There is an urgent need for more effective therapies in this large subgroup of GBM . Since results of phase II trials 
    Output:
    
Significant design heterogeneity was noted in the included studies , especially in the response assessment criteria used .
In patients with newly diagnosed GBM , the use of antiangiogenic therapy does not improve survival , despite evidence of improved progression-free survival .
Thus at this time , evidence is insufficient to support the use of antiangiogenic therapy in patients with newly diagnosed GBM on the basis of effects on survival .
Bevacizumab may confer a progression-free survival benefit in GBM ; however evidence in favour of using other antiangiogenic therapies in recurrent GBM is insufficient .
Although bevacizumab appears to prolong progression-free survival in newly diagnosed and recurrent GBM , the impact of this on quality of life remains unclear .
Not addressed here is whether subsets of patients with newly diagnosed GBM may benefit from antiangiogenic therapies and whether these therapies are useful in other high- grade glioma histologies