***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: BACKGROUND The OPTIMAL study found that erlotinib improved progression-free survival ( PFS ) versus st and ard chemotherapy in Chinese patients with advanced EGFR mutation-positive non-small-cell lung cancer ( NSCLC ) . This report describes the quality of life ( QoL ) and up date d PFS analyses from this study . PATIENTS AND METHODS Chinese patients ≥ 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR ( exon 19 deletion or exon 21 L858R point mutation ) received erlotinib ( 150 mg/day ; n = 82 ) or gemcitabine-carboplatin ( n = 72 ) . The primary efficacy end point was PFS ; QoL was assessed using the Functional Assessment of Cancer Therapy-Lung ( FACT-L ) question naire , Trial Outcome Index ( TOI ) and Lung Cancer Subscale ( LCS ) . RESULTS Patients receiving erlotinib experienced clinical ly relevant improvements in QoL compared with the chemotherapy group in total FACT-L , TOI and LCS ( P < 0.0001 for all scales ) . Erlotinib scored better than chemotherapy for all FACT-L subscales from baseline to cycles 2 and 4 ( non-significant ) . In the up date d analysis , PFS was significantly longer for erlotinib than chemotherapy ( median PFS 13.7 versus 4.6 months ; HR = 0.164 , 95 % CI = 0.105 - 0.256 ; P < 0.0001 ) , which was similar to the previously reported primary analysis . CONCLUSION Erlotinib  improves QoL compared with st and ard chemotherapy in the first-line treatment of patients with EGFR mutation-positive advanced NSCLC BACKGROUND Bevacizumab and erlotinib target different tumour growth pathways with little overlap in their toxic-effect profiles . On the basis of promising results from a phase 1/2 trial assessing safety and activity of erlotinib plus bevacizumab for recurrent or refractory non-small-cell lung cancer ( NSCLC ) , we aim ed to assess efficacy and safety of this combination in a phase 3 trial . METHODS In our double-blind , placebo-controlled , r and omised phase 3 trial ( BeTa ) , we enrolled patients with recurrent or refractory NSCLC who presented to 177 study sites in 12 countries after failure of first-line treatment . Patients were r and omly allocated in a one-to-one ratio to receive erlotinib plus bevacizumab ( bevacizumab group ) or erlotinib plus placebo ( control group ) according to a computer-generated r and omisation sequence by use of an interactive voice response system . The primary endpoint was overall survival in all enrolled patients . Patients , study staff , and investigators were masked to treatment assignment . We assessed safety by calculation of incidence of adverse events and tissue was collected for biomarker analyses . This trial is registered with Clinical Trials.gov , number NCT00130728 . FINDINGS Overall survival did not differ between 317 controls and 319 patients in the bevacizumab group ( hazard ratio [ HR ] 0·97 , 95 % CI 0·80 - 1·18 , p=0·7583 ) . Median overall survival was 9·3 months ( IQR 4·1 - 21·6 ) for patients in the bevacizumab group compared with 9·2 months ( 3·8 - 20·2 ) for controls . Progression-free survival seemed to be longer in the bevacizumab group ( 3·4 months [ 1·4 - 8·4 ] ) than in the control group ( 1·7 months [ 1·3 - 4·1 ] ; HR 0·62 , 95 % CI 0·52 - 0·75 ) and objective response rate suggested some clinical activity of bevacizumab and erlotinib . However , these secondary endpoint differences could not be defined as significant because the study prespecified that the primary endpoint had to be significant before testing of secondary endpoints could be done , to control type I error rate . In the bevacizumab group , 130 ( 42 % ) of 313 patients with safety  data had a serious adverse event , compared with 114 ( 36 % ) controls . There were 20 ( 6 % ) grade 5 adverse events , including two arterial thromboembolic events , in the bevacizumab group , and 14 ( 4 % ) in the control group . INTERPRETATION Addition of bevacizumab to erlotinib does not improve survival in patients with recurrent or refractory NSCLC . FUNDING Genentech BACKGROUND With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer ( NSCLC ) , median progression-free survival has been extended to about 12 months . Nevertheless , new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population . We aim ed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease . METHODS In this open-label , r and omised , multicentre , phase 2 study , patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations , Eastern Cooperative Oncology Group performance status 0 or 1 , and no previous chemotherapy for advanced disease received erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity . The primary endpoint was progression-free survival , as determined by an independent review committee . R and omisation was done with a dynamic allocation method , and the analysis used a modified intention-to-treat approach , including all patients who received at least one dose of study treatment and had tumour assessment at least once after r and omisation . This study is registered with the Japan Pharmaceutical Information Center , number JapicCTI-111390 . FINDINGS Between Feb 21 , 2011 , and March 5 , 2012 , 154 patients were enrolled . 77 were r and omly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone , of whom 75 patients in the erlotinib plus bevacizumab  group and 77 in the erlotinib alone group were included in the efficacy analyses . Median progression-free survival was 16·0 months ( 95 % CI 13·9 - 18·1 ) with erlotinib plus bevacizumab and 9·7 months ( 5·7 - 11·1 ) with erlotinib alone ( hazard ratio 0·54 , 95 % CI 0·36 - 0·79 ; log-rank test p=0·0015 ) . The most common grade 3 or worse adverse events were rash ( 19 [ 25 % ] patients in the erlotinib plus bevacizumab group vs 15 [ 19 % ] patients in the erlotinib alone group ) , hypertension ( 45 [ 60 % ] vs eight [ 10 % ] ) , and proteinuria ( six [ 8 % ] vs none ) . Serious adverse events occurred at a similar frequency in both groups ( 18 [ 24 % ] patients in the erlotinib plus bevacizumab group and 19 [ 25 % ] patients in the erlotinib alone group ) . INTERPRETATION Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC . Further investigation of the regimen is warranted . FUNDING Chugai Pharmaceutical Co Relative to normal tissues , tumor microcirculation exhibits high structural and functional heterogeneity leading to hypoxic regions and impairing treatment efficacy . Here , computational simulations of blood vessel structural adaptation are used to explore the hypothesis that abnormal adaptive responses to local hemodynamic and metabolic stimuli contribute to aberrant morphological and hemodynamic characteristics of tumor microcirculation . Topology , vascular diameter , length , and red blood cell velocity of normal mesenteric and tumor vascular networks were recorded by intravital microscopy . Computational models were used to estimate hemodynamics and oxygen distribution and to simulate vascular diameter adaptation in response to hemodynamic , metabolic and conducted stimuli . The assumed sensitivity to hemodynamic and conducted signals , the vascular growth tendency , and the r and om variability of vascular responses were altered to simulate ‘ normal ’ and ‘ tumor ’ adaptation modes . The heterogeneous properties of vascular networks were characterized by diameter mismatch at vascular branch points ( d3 var ) and deficit of oxygen delivery relative to dem and ( O2def ) . In the tumor , d3 var and O2def were higher ( 0.404 and 0.182 ) than in normal networks ( 0.278 and 0.099 ) . Simulated remodeling of the tumor network with ‘ normal ’ parameters gave low values ( 0.288 and 0.099 ) . Conversely , normal networks attained tumor-like characteristics ( 0.41 and 0.179 ) upon adaptation with ‘ tumor ’ parameters , including low conducted sensitivity , increased growth tendency , and elevated r and om biological variability . It is concluded that the deviant properties of tumor microcirculation may result largely from defective structural adaptation , including strongly reduced responses to conducted stimuli BACKGROUND Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer ( NSCLC ) with activating EGFR mutations . We aim ed to assess the safety and efficacy of erlotinib compared with st and ard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC . METHODS We undertook the open-label , r and omised phase 3 EURTAC trial at 42 hospitals in France , Italy , and Spain . Eligible participants were adults ( > 18 years ) with NSCLC and EGFR mutations ( exon 19 deletion or L858R mutation in exon 21 ) with no history of chemotherapy for metastatic disease ( neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed ) . We r and omly allocated participants ( 1:1 ) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of st and ard intravenous chemotherapy of cisplatin 75 mg/m(2 ) on day 1 plus docetaxel ( 75 mg/m(2 ) on day 1 ) or gemcitabine ( 1250 mg/m(2 ) on days 1 and 8) . Carboplatin ( AUC 6 with docetaxel 75 mg/m(2 ) or AUC 5 with gemcitabine 1000 mg/m(2 ) ) was allowed in patients unable to have cisplatin . Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status ( 0 vs 1 vs 2 ) . The primary endpoint was progression-free survival ( PFS ) in the intention-to-treat population . We assessed safety in all patients who received study drug ( ≥ 1 dose ) . This study is registered with Clinical Trials.gov , number NCT00446225 . FINDINGS Between Feb 15 , 2007 , and Jan 4 , 2011 , 174 patients with EGFR mutations were enrolled . One patient received treatment before r and omisation and was thus withdrawn from the study ; of the remaining patients , 86 were r and omly assigned to receive erlotinib and 87 to receive st and ard chemotherapy . The preplanned interim analysis showed that the study met its primary endpoint ; enrolment was halted , and full evaluation of the results was recommended . At data cutoff ( Jan 26 , 2011 ) , median PFS was 9·7 months ( 95 % CI 8·4 - 12·3 ) in the erlotinib group , compared with 5·2 months ( 4·5 - 5·8 ) in the st and ard chemotherapy group ( hazard ratio 0·37 , 95 % CI 0·25 - 0·54 ; p < 0·0001 ) . Main grade 3 or 4 toxicities were rash ( 11 [ 13 % ] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group ) , neutropenia ( none vs 18 [ 22 % ] ) , anaemia ( one [ 1 % ] vs three [ 4 % ] ) , and increased amino-transferase concentrations ( two [ 2 % ] vs 0 ) . Five ( 6 % ) patients on erlotinib  had treatment-related severe adverse events compared with 16 patients ( 20 % ) on chemotherapy . One patient in the erlotinib group and two in the st and ard chemotherapy group died from treatment-related causes . INTERPRETATION Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors . FUNDING Spanish Lung Cancer Group , Roche Farma , Hoffmann-La Ro 
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In addition , diarrhea , hypertension , thrombocytopenia , neutropenia , fatigue , rash , and dermatitis acneiform were significantly increased in patients treated with angiogenesis inhibitors .
Thus , EGFR-TKIs combined with angiogenesis inhibitors were superior to EGFR-TKIs alone in advanced NSCLC due to their effects on PFS , ORR and DCR , but the increased incidence of AEs had an influence on the tolerability of this combination therapy