***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: Treatment of glioblastoma ( GBM ) , the most common primary malignant brain tumor in adults , remains a significant unmet need in oncology . Historically , cytotoxic treatments provided little durable benefit , and tumors recurred within several months . This has spurred a substantial research effort to establish more effective therapies for both newly diagnosed and recurrent GBM . In this context , antiangiogenic therapy emerged as a promising treatment strategy because GBMs are highly vascular tumors . In particular , GBMs overexpress vascular endothelial growth factor ( VEGF ) , a proangiogenic cytokine . Indeed , many studies have demonstrated promising radiographic response rates , delayed tumor progression , and a relatively safe profile for anti-VEGF agents . However , r and omized phase III trials conducted to date have failed to show an overall survival benefit for antiangiogenic agents alone or in combination with chemoradiotherapy . These results indicate that antiangiogenic agents may not be beneficial in unselected population s of patients with GBM . Unfortunately , biomarker development has lagged behind in the process of drug development , and no vali date d biomarker exists for patient stratification . However , hypothesis-generating data from phase II trials that reveal an association between increased perfusion and /or oxygenation ( ie , consequences of vascular normalization ) and survival suggest that early imaging biomarkers could help identify the subset of patients who most likely will benefit from anti-VEGF agents . In this article , we discuss the lessons learned from the trials conducted to date and how we could potentially use recent advances in GBM biology and imaging to improve outcomes of patients with GBM who receive antiangiogenic therapy BACKGROUND Treatment options for recurrent glioblastoma are scarce , with second-line chemotherapy showing only modest activity against the tumour . Despite the absence of well controlled trials , bevacizumab is widely used in the treatment of recurrent glioblastoma . Nonetheless , whether the high response rates reported after treatment with this drug translate into an overall survival benefit remains unclear . We report the results of the first r and omised controlled phase 2 trial of bevacizumab in recurrent glioblastoma . METHODS The BELOB trial was an open-label , three-group , multicentre phase 2 study undertaken in 14 hospitals in the Netherl and s. Adult patients ( ≥18 years of age ) with a first recurrence of a glioblastoma after temozolomide chemoradiotherapy  were r and omly allocated by a web-based program to treatment with oral lomustine 110 mg/m(2 ) once every 6 weeks , intravenous bevacizumab 10 mg/kg once every 2 weeks , or combination treatment with lomustine 110 mg/m(2 ) every 6 weeks and bevacizumab 10 mg/kg every 2 weeks . R and omisation of patients was stratified with a minimisation procedure , in which the stratification factors were centre , Eastern Cooperative Oncology Group performance status , and age . The primary outcome was overall survival at 9 months , analysed by intention to treat . A safety analysis was planned after the first ten patients completed two cycles of 6 weeks in the combination treatment group . This trial is registered with the Nederl and s Trial Register ( www.trialregister.nl , number NTR1929 ) . FINDINGS Between Dec 11 , 2009 , and Nov 10 , 2011 , 153 patients were enrolled . The preplanned safety analysis was done after eight patients had been treated , because of haematological adverse events ( three patients had grade 3 thrombocytopenia and two had grade 4 thrombocytopenia ) which reduced bevacizumab dose intensity ; the lomustine dose in the combination treatment group was thereafter reduced to 90 mg/m(2 ) . Thus , in addition to the eight patients who were r and omly assigned to receive bevacizumab plus lomustine 110 mg/m(2 ) , 51 patients were assigned to receive bevacizumab alone , 47 to receive lomustine alone , and 47 to receive bevacizumab plus lomustine 90 mg/m(2 ) . Of these patients , 50 in the bevacizumab alone group , 46 in the lomustine alone group , and 44 in the bevacizumab and lomustine 90 mg/m(2 ) group were eligible for analyses . 9-month overall survival was 43 % ( 95 % CI 29 - 57 ) in the lomustine group , 38 % ( 25 - 51 ) in the bevacizumab group , 59 % ( 43 - 72 ) in the bevacizumab and lomustine 90 mg/m(2 ) group , 87 % ( 39 - 98 ) in the bevacizumab and lomustine 110 mg/m(2 ) group , and 63 % ( 49 - 75 ) for the combined bevacizumab and lomustine groups . After the reduction in lomustine dose in the combination group , the combined treatment was well tolerated . The most frequent grade 3 or worse toxicities were hypertension ( 13 [ 26 % ] of 50 patients in the bevacizumab group , three [ 7 % ] of 46 in the lomustine group , and 11 [ 25 % ] of 44 in the bevacizumab and lomustine 90 mg/m(2 ) group ) , fatigue ( two [ 4 % ] , four [ 9 % ] , and eight [ 18 % ] ) , and infections ( three [ 6 % ] , two [ 4 % ] , and five [ 11 % ] ) . At the time of this analysis , 144/148 ( 97 % ) of patients had died and three ( 2 % ) were still on treatment . INTERPRETATION The combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies . However , the results in the bevacizumab alone group do not justify further studies of this treatment . FUNDING Roche Nederl and and KWF Kankerbestrijding Significance This study demonstrates that antiangiogenic therapy increases tumor blood perfusion in a subset of newly diagnosed glioblastoma patients , and that it is these patients who survive longer when this expensive and potentially toxic therapy is combined with st and ard radiation and chemotherapy . This study provides fresh insights into the selection of glioblastoma patients most likely to benefit from antiangiogenic treatments . Antiangiogenic therapy has shown clear activity and improved survival benefit for certain tumor types . However , an incomplete underst and ing of the mechanisms of action of antiangiogenic agents has hindered optimization and broader application of this new therapeutic modality . In particular , the impact of antiangiogenic therapy on tumor blood flow and oxygenation status ( i.e. , the role of vessel pruning versus normalization ) remains controversial . This controversy has become critical as multiple phase III trials of anti-VEGF agents combined with cytotoxics failed to show overall survival benefit in newly diagnosed glioblastoma ( nGBM ) patients and several other cancers . Here , we shed light on mechanisms of nGBM response to cediranib , a pan-VEGF receptor tyrosine kinase inhibitor , using MRI techniques and blood biomarkers in prospect i ve phase II clinical trials of cediranib with chemoradiation vs. chemoradiation alone in nGBM patients . We demonstrate that improved perfusion occurs only in a subset of patients in  cediranib-containing  regimens , and is associated with improved overall survival in these nGBM patients . Moreover , an increase in perfusion is associated with improved tumor oxygenation status as well as with pharmacodynamic biomarkers , such as changes in plasma placenta growth factor and sVEGFR2 . Finally , treatment resistance was associated with elevated plasma IL-8 and sVEGFR1 posttherapy . In conclusion , tumor perfusion changes after antiangiogenic therapy may distinguish responders vs. nonresponders early in the course of this expensive and potentially toxic form of therapy , and these results may provide new insight into the selection of glioblastoma patients most likely to benefit from anti-VEGF treatments BACKGROUND Survival outcomes for patients with glioblastoma remain poor , particularly for patients with unmethylated O(6)-methylguanine-DNA methyltransferase ( MGMT ) gene promoter . This phase II , r and omized , open-label , multicenter trial investigated the efficacy and safety of 2 dose regimens of the selective integrin inhibitor cilengitide combined with st and ard chemoradiotherapy in patients with newly diagnosed glioblastoma and an unmethylated MGMT promoter . METHODS Overall , 265 patients were r and omized ( 1:1:1 ) to st and ard cilengitide ( 2000 mg 2 × /wk ; n = 88 ) , intensive cilengitide ( 2000 mg 5 × /wk during wk 1 - 6 , thereafter 2 × /wk ; n = 88 ) , or a control arm ( chemoradiotherapy alone ; n = 89 ) . Cilengitide was administered intravenously in combination with daily temozolomide ( TMZ ) and concomitant radiotherapy ( RT ; wk 1 - 6 ) , followed by TMZ maintenance therapy ( TMZ/RT→TMZ ) . The primary endpoint was overall survival ; secondary endpoints included progression-free survival , pharmacokinetics , and safety and tolerability . RESULTS Median overall survival was 16.3 months in the st and ard cilengitide arm ( hazard ratio [ HR ] , 0.686 ; 95 % CI : 0.484 , 0.972 ; P = .032 ) and 14.5 months in the intensive cilengitide arm ( HR , 0.858 ; 95 % CI : 0.612 , 1.204 ; P = .3771 ) versus 13.4 months in the control arm . Median progression-free survival assessed per independent review committee was 5.6 months ( HR , 0.822 ; 95 % CI : 0.595 , 1.134 ) and 5.9 months ( HR , 0.794 ; 95 % CI : 0.575 , 1.096 ) in the st and ard and intensive cilengitide arms , respectively , versus 4.1 months in the control arm . Cilengitide was well tolerated . CONCLUSIONS St and ard and intensive cilengitide dose regimens were well tolerated in combination with TMZ/RT→TMZ . Inconsistent overall survival and progression-free survival outcomes and a limited sample size did not allow firm conclusions regarding clinical efficacy in this exploratory phase II study PURPOSE This phase III open-label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma ( WHO grade 4 ) . PATIENTS AND METHODS Patients were r and omly assigned 2:1 to receive 6-week cycles of enzastaurin 500 mg/d ( 1,125-mg loading dose , day 1 ) or lomustine ( 100 to 130 mg/m(2 ) , day 1 ) . Assuming a 45 % improvement in progression-free survival ( PFS ) , 397 patients were required to provide 80 % power to achieve statistical significance at a one-sided level of .025 . RESULTS Enrollment was terminated at 266 patients ( enzastaurin , n = 174 ; lomustine , n = 92 ) after a planned interim analysis for futility . Patient characteristics were balanced between arms . Median PFS ( 1.5 v 1.6 months ; hazard ratio [ HR ] = 1.28 ; 95 % CI , 0.97 to 1.70 ) , overall survival ( 6.6 v 7.1 months ; HR = 1.20 ; 95 % CI , 0.88 to 1.65 ) , and 6-month PFS rate ( P = .13 ) did not differ significantly between enzastaurin and lomustine , respectively . Stable disease occurred in 38.5 % and 35.9 % of patients and objective response occurred in 2.9 % and 4.3 % of patients , respectively . Time to deterioration of physical and functional well-being and symptoms did not differ between arms ( HR = 1.12 ; P = .54 ) . Four patients discontinued enzastaurin because of drug-related serious adverse events ( AEs ) . Eleven patients treated with enzastaurin  died on study ( four because of AEs ; one was drug-related ) . All four deaths that occurred in patients receiving lomustine were disease-related . Grade 3 to 4 hematologic toxicities were significantly higher with lomustine ( 46 events ) than with enzastaurin ( one event ; P < or = .001 ) . CONCLUSION Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma 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 
    Output:
    
antiangiogenic drugs did not improve overall survival in glioblastoma patients , either as first or second-line treatment , and either as single agent or in combination with chemotherapy .
Among antiangiogenic drugs , only bevacizumab improved progression-free survival regardless of treatment line , both as single agent or in combination with chemotherapy