***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: Our objective is to assess treatment efficacy , safety and pattern of response and recurrence in patients with recurrent high- grade glioma treated with bevacizumab and irinotecan .  We review ed retrospectively 51 patients with recurrent high- grade glioma treated with this combination at the Henry Ford Hermelin Brain Tumor Center from 11/15/2005 to 04/01/2008 . The 6-month progression-free survival ( PFS ) for anaplastic gliomas ( AGs ) was 78.6 and 63.7 % for glioblastoma . The median PFS was 13.4 months for AG and 7.6 months for those with glioblastoma . The overall survival rate ( OS ) at 6 months was 85.7 % for AG and 78.0 % for glioblastoma . The 12-month OS was 77.9 % for AG and 42.6 % for glioblastoma . The median OS time for AGs was not reached and was 11.5 months for those with glioblastoma . Thirty-six out of 51 ( 70.59 % ) patients demonstrated partial ( 32/51 ) or complete ( 4/51 ) radiographic response to treatment and 8/51 ( 15.69 % ) remained stable . Of the 38 who demonstrated progression on post-gadolinium studies , 23 showed distant progression with or without local recurrence . Seven patients showed progression on FLAIR without concordant findings on post-Gd sequences . Six patients ( 11.76 % ) discontinued treatment due to a treatment-emergent adverse event , including one with end-stage renal failure and another with gastric perforation . No symptomatic intracranial hemorrhages were reported . Patients with recurrent high- grade glioma treated with bevacizumab plus irinotecan demonstrate an excellent radiographic response rate and improved clinical outcome when compared to historical data . The high rate of distant tumor progression suggests that tumors may adapt to inhibition of angiogenesis by increased infiltration and vascular co-option PURPOSE This open-label , prospect i ve , multicenter single-arm phase II study combined bevacizumab ( BV ) with radiation therapy ( RT ) and temozolomide ( TMZ ) for the treatment of newly diagnosed glioblastoma ( GBM ) . The objectives were to determine the efficacy of this treatment combination and the associated toxicity . PATIENTS AND METHODS Seventy patients with newly diagnosed GBM were enrolled between August 2006 and November 2008 . Patients received st and ard RT starting within 3 to 6 weeks after surgery with concurrent administration of daily TMZ and biweekly BV . After completion of RT , patients resumed TMZ for 5 days every 4 weeks and continued biweekly BV . MGMT promoter methylation was assessed on patient tumor tissue . A University of California , Los Angeles/Kaiser Permanente Los Angeles ( KPLA ) control cohort of newly diagnosed patients treated with first-line RT and TMZ who had mostly received BV at recurrence was derived for comparison . RESULTS The overall survival ( OS ) and progression-free survival ( PFS ) were 19.6 and 13.6 months , respectively , compared to 21.1 and 7.6 months in the University of California , Los Angeles/KPLA control cohort , and 14.6 and 6.9 months in the European Organisation for Research and Treatment of Cancer-National Cancer Institute of Canada cohort . Correlation of MGMT promoter methylation and improved OS and PFS was retained in the study group . Comparative subset analysis showed that poor prognosis patients ( recursive partitioning analysis class V/VI ) may derive an early benefit from the use of first-line BV . Toxicity attributable to RT/TMZ was similar , and additional toxicities were consistent with those reported in other BV trials . CONCLUSION Patients treated with  BV and TMZ  during and after RT showed improved PFS without improved OS compared to the University of California , Los Angeles/KPLA control group . Additional studies are warranted to determine if BV administered first-line improves survival compared to BV at recurrence The aim of this clinical trial was to investigate safety and efficacy when combining cetuximab with bevacizumab and irinotecan in patients with recurrent primary glioblastoma multiforme ( GBM ) . Patients were included with recurrent primary GBM and progression within 6 months of ending st and ard treatment ( radiotherapy and temozolomide ) .  Bevacizumab and irinotecan were administered IV every 2 weeks . The first 10 patients received bevacizumab 5 mg/kg , but this was increased to 10 mg/kg after interim safety analysis . Irinotecan dose was based on whether patients were taking enzyme-inducing antiepileptic drugs or not : 340 and 125 mg/m(2 ) , respectively . Cetuximab 400 mg/m(2 ) as loading dose followed by 250 mg/m(2 ) weekly was administered IV . Forty-three patients were enrolled in the trial , of which 32 were available for response .  Radiographic responses were noted in 34 % , of which 2 patients had complete responses and 9 patients had partial responses . The 6-month progression-free survival probability was 30 % and median overall survival was 29 weeks ( 95 % CI : 23 - 37 weeks ) . One patient had lacunar infa rct ion , 1 patient had multiple pulmonary embolisms , and 3 patients had grade 3 skin toxicity , for which 1 patient needed plastic surgery . One patient was excluded due to suspicion of interstitial lung disease . Three patients had deep-vein thrombosis ; all continued on study after adequate treatment . Cetuximab in combination with bevacizumab and irinotecan in recurrent GBM is well tolerated except for skin toxicity , with an encouraging response rate . However , the efficacy data do not seem to be superior compared with results with bevacizumab and irinotecan alone Vascular endothelial growth factor ( VEGF ) and epidermal growth factor receptor ( EGFR ) signaling are established contributors to malignant glioma ( MG ) biology . We , therefore , evaluated bevacizumab , a humanized anti-VEGF monoclonal antibody , in combination with the EGFR tyrosine kinase inhibitor erlotinib , in this phase 2 study for recurrent MG patients ( www . Clinical Trials.gov , NCT00671970 ) . Fifty-seven patients ( n = 25 , glioblastoma [ GBM ] ; n = 32 , anaplastic glioma [ AG ] ) were enrolled . The primary endpoint was 6-month progression-free survival ( PFS-6 ) . Overall survival ( OS ) , radiographic response , pharmacokinetics , and correlative biomarkers were the secondary endpoints . Patients were stratified based on the concurrent use of enzyme-inducing antiepileptic drugs ( EIAEDs ) . Bevacizumab ( 10 mg/kg ) was given intravenously every 2 weeks . Erlotinib was orally administered daily at 200 mg/day for patients not on EIAEDs and 500 mg/day for patients on EIAEDs . PFS-6 and median OS were 28 % and 42 weeks for GBM patients and 44 % and 71 weeks for AG patients , respectively . Twelve ( 48 % ) GBM patients and 10 ( 31 % ) AG patients achieved a radiographic response .  Erlotinib pharmacokinetic exposures were comparable between EIAED and non-EIAED groups . Rash , mucositis , diarrhea , and fatigue were common but mostly grade s 1 and 2 . Among GBM patients , grade 3 rash , observed in 32 % , was associated with survival benefit , whereas elevated hypoxia-inducible factor-2 alpha and VEGF receptor-2 levels were associated with poor survival . Bevacizumab plus erlotinib was adequately tolerated in recurrent MG patients . However , this regimen was associated with similar PFS benefit and radiographic response when compared with other historical bevacizumab-containing regimens The objective of this phase II single-arm study was to evaluate the efficacy and safety of pazopanib , a multi-targeted tyrosine kinase inhibitor , against vascular endothelial growth factor receptor (VEGFR)-1 , -2 , and -3 , platelet-derived growth factor receptor-alpha and -beta , and c-Kit , in recurrent glioblastoma . Patients with < or = 2 relapses and no prior anti-VEGF/VEGFR therapy were treated with pazopanib 800 mg daily on 4-week cycles without planned interruptions . Brain magnetic resonance imaging and clinical re assessment were made every 8 weeks . The primary endpoint was efficacy as measured by 6-month progression-free survival ( PFS6 ) . Thirty-five GBM patients with a median age of 53 years and median Karnofsky performance scale of 90 were accrued .  Grade 3/4 toxicities included leukopenia ( n = 1 ) , lymphopenia ( n = 2 ) , thrombocytopenia ( n = 1 ) , ALT elevation ( n = 3 ) , AST elevation ( n = 1 ) , CNS hemorrhage ( n = 1 ) , fatigue ( n = 1 ) , and thrombotic/embolic events ( n = 3 ) ; 8 patients required dose reduction . Two patients had a partial radiographic response by st and ard bidimensional measurements , whereas 9 patients ( 6 at the 8-week point and 3 only within the first month of treatment ) had decreased contrast enhancement , vasogenic edema , and mass effect but < 50 % reduction in tumor . The median PFS was 12 weeks ( 95 % confidence interval [ CI ] : 8 - 14 weeks ) and only 1 patient had a PFS time > or = 6 months ( PFS6 = 3 % ) . Thirty patients ( 86 % ) had died and median survival was 35 weeks ( 95 % CI : 24 - 47 weeks ) . Pazopanib was reasonably well tolerated with a spectrum of toxicities similar to other anti-VEGF/VEGFR agents . Single-agent pazopanib did not prolong PFS in this patient population but showed in situ biological activity as demonstrated by radiographic responses . Clinical Trials.gov identifier : NCT00459381 Purpose : To determine if the addition of bevacizumab to radiation therapy and temozolomide , followed by bevacizumab , temozolomide , and irinotecan , for newly diagnosed glioblastoma patients is safe and effective . Experimental Design : A total of 75 patients with newly diagnosed glioblastoma were enrolled in the phase II trial that investigated the addition of bevacizumab to st and ard radiation therapy and daily temozolomide followed by the addition of bevacizumab and irinotecan to adjuvant temozolomide . The bevacizumab was given at 10 mg/kg every 14 days beginning a minimum of 4 weeks postcraniotomy . Two weeks after radiation therapy , the patients began 6 to 12 cycles of 5-day temozolomide with bevacizumab and irinotecan every 14 days . The primary endpoint was the proportion of patients alive 16 months after informed consent . Results : The therapy had moderate toxicity . Three patients , one of whom had a grade 2 central nervous system hemorrhage , came off study during radiation therapy . Seventy patients started the postradiation therapy , and 16 ( 23 % ) terminated this adjuvant therapy early because of toxicity . The median overall survival was 21.2 months ( 95 % CI : 17.2–25.4 ) , and 65 % of the patients were alive at 16 months ( 95 % CI : 53.4–74.9 ) . The median progression-free survival was 14.2 months ( 95 % CI : 12–16 ) . Conclusion : The addition of bevacizumab to st and ard radiation therapy and temozolomide , followed by bevacizumab , irinotecan , and temozolomide , for the treatment of newly diagnosed glioblastoma has moderate toxicity and may improve efficacy compared with historical controls . The results from phase III trials are required before the role of bevacizumab for newly diagnosed glioblastoma is established . Clin Cancer Res ; 17(12 ) ; 4119–24 . © 2011 AACR PURPOSE To determine the safety of the addition of bevacizumab to st and ard radiation therapy and daily temozolomide for newly diagnosed glioblastoma multiforme ( GBM ) . METHODS AND MATERIAL S A total of 125 patients with newly diagnosed GBM were enrolled in the study , and received st and ard radiation therapy and daily temozolomide .  All patients underwent a craniotomy and were at least 2 weeks postoperative .  Radiation therapy was administered in 1.8-Gy fractions , with the clinical target volume for the primary course treated to a dose of 45 to 50.4 Gy , followed by a boost of 9 to 14.4 Gy , to a total dose of 59.4 Gy . Patients received temozolomide at 75 mg/m(2 ) daily throughout the course of radiation therapy . Bevacizumab was given at 10 mg/kg intravenously every 14 days , beginning a minimum of 4 weeks postoperatively . RESULTS Of 
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The use of bevacizumab combined with chemo-radiotherapy seems to be associated with a higher risk for VTE compared to patients receiving antiangiogenic therapy alone .
The associated use of anticoagulants and bevacizumab far increases the risk of developing CNS and non-CNS bleeding higher than grade 3 , compared to patients receiving bevacizumab alone