***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 effects of vascular endothelial growth factor ( VEGF ) blockade on the vascular biology of human tumors are not known . Here we show here that a single infusion of the VEGF-specific antibody bevacizumab decreases tumor perfusion , vascular volume , microvascular density , interstitial fluid pressure and the number of viable , circulating endothelial and progenitor cells , and increases the fraction of vessels with pericyte coverage in rectal carcinoma patients . These data indicate that VEGF blockade has a direct and rapid antivascular effect in human tumors PURPOSE Mutations affecting the KRAS gene are established predictive markers of outcome with anti-epithelial growth factor receptor ( EGFR ) antibodies in advanced colorectal cancer ( CRC ) . The relevance of these markers for anti-vascular endothelial growth factor ( VEGF ) therapy is controversial . This analysis was performed to assess the predictive and prognostic impact of KRAS and BRAF gene mutation status in patients receiving capecitabine with bevacizumab ( CG ) or capecitabine without bevacizumab in the phase III AGITG MAX ( Australasian Gastrointestinal Trials Group MAX ) study . PATIENTS AND METHODS Mutation status was determined for 315 ( 66.9 % ) of the original 471 patients . Mutation status was correlated with efficacy outcomes ( response rate , progression-free survival [ PFS ] , and overall survival [ OS ] ) , and a predictive analyses was undertaken . RESULTS Mutations in KRAS and BRAF genes were observed in 28.8 % and 10.6 % of patients , respectively . KRAS gene mutation status ( wild type [ WT ] v mutated [ MT ] ) had no prognostic impact for PFS ( hazard ratio [ HR ] , 0.89 ; CI , 0.69 to 1.14 ) or OS ( HR , 0.97 ; CI , 0.73 to 1.28 ) . BRAF mutation status ( WT v MT ) was not prognostic for PFS ( HR , 0.80 ; CI , 0.54 to 1.18 ) but was prognostic for OS ( HR , 0.49 ; CI , 0.33 to 0.73 ; P = .001 ) . By using the comparison of capecitabine versus capecitabine and bevacizumab ( CB ) and CB plus mitomycin ( CBM ) , KRAS gene mutation status was not predictive of the effectiveness of  bevacizumab for PFS or OS ( test for interaction P = .95 and 0.43 , respectively ) . Similarly , BRAF gene mutation status was not predictive of the effectiveness of bevacizumab for PFS or OS ( test for interaction P = .46 and 0.32 , respectively ) . CONCLUSION KRAS gene mutation status was neither prognostic for OS nor predictive of bevacizumab outcome in patients with advanced CRC . BRAF gene mutation status was prognostic for OS but was not predictive of outcome with bevacizumab This study evaluates the efficacy of capecitabine using data from a large , well-characterised population of patients with metastatic colorectal cancer ( mCRC ) treated in two identically design ed phase III studies . A total of 1207 patients with previously untreated mCRC were r and omised to either oral capecitabine ( 1250 mg m−2 twice daily , days 1−14 every 21 days ; n=603 ) or intravenous ( i.v . ) bolus 5-fluorouracil/leucovorin ( 5-FU/LV ; Mayo Clinic regimen ; n=604 ) . Capecitabine demonstrated a statistically significant superior response rate compared with 5-FU/LV ( 26 vs 17 % ; P<0.0002 ) . Subgroup analysis demonstrated that capecitabine consistently result ed in superior response rates ( P<0.05 ) , even in patient subgroups with poor prognostic indicators . The median time to response and duration of response were similar and time to progression ( TTP ) was equivalent in the two arms ( hazard ratio ( HR ) 0.997 , 95 % confidence interval ( CI ) 0.885–1.123 , P=0.95 ; median 4.6 vs 4.7 months with capecitabine and 5-FU/LV , respectively ) . Multivariate Cox regression analysis identified younger age , liver metastases , multiple metastases and poor Karnofsky Performance Status as independent prognostic indicators for poor TTP . Overall survival was equivalent in the two arms ( HR 0.95 , 95 % CI 0.84–1.06 , P=0.48 ; median 12.9 vs 12.8 months , respectively ) . Capecitabine results in superior response rate , equivalent TTP and overall survival , an improved safety profile and improved convenience compared with i.v . 5-FU/LV as first-line treatment for MCRC . For patients in whom fluoropyrimidine monotherapy is indicated , capecitabine should be strongly considered . Following encouraging results from phase I and II trials , r and omised trials are evaluating capecitabine in combination with irinotecan , oxaliplatin and radiotherapy . Capecitabine is a suitable replacement for i.v . 5-FU as the backbone of colorectal cancer therapy Objective : The objective of this phase III trial was to compare chemotherapy combined with bevacizumab versus chemotherapy alone in the treatment of patients with advanced colorectal cancer . Methods : From September 2004 till September 2008 , 222 treatment-naive patients were enrolled and divided into 2 arms : 114 arm A patients were treated with leucovorin , 5-fluorouracil plus irinotecan in combination with bevacizumab , and 108 arm B patients were treated as above without bevacizumab .  All patients were stage IV with histologically confirmed adenocarcinoma . Results : The median overall survival of arm A patients was 22.0 months ( 95 % CI : 18.1–25.9 ) and 25.0 months ( CI : 18.1–31.9 ) for arm B patients . There was no statistically significant difference between the 2 arms ( p = 0.1391 ) . No statistically significant difference between the 2 arms regarding the response ratewas observed : partial response , 42 patients ( 36.8 % ) and 38 patients ( 35.2 % ) for arms A and B , respectively . Hematologic toxicity did not differ in the comparison of the 2 arms . Nonhematologic toxicity in arm A involved hypertension in 23 ( 20.2 % ) of the patients and proteinuria in 7 ( 6.1 % ) ; 3 patients experienced hemorrhage and 1 patient intestinal perforation . None of these side effects was observed in arm B patients . Conclusion : No statistically significant difference in median overall survival in patients with advanced colorectal cancer treated with bevacizumab plus a combination therapy ( arm A ) and those treated with the combination only , without bevacizumab ( arm B ) , was observed This multicenter , Phase II trial was performed to evaluate the antitumor activity and toxicity of irinotecan ( CPT‐11 ) in patients with metastatic colorectal carcinoma that had recurred or progressed after 5‐fluorouracil (5‐FU)‐based chemotherapy PURPOSE Tumor angiogenesis mediated by vascular endothelial growth factor ( VEGF ) is inhibited by the recombinant humanized ( rhu ) monoclonal antibody ( MAb ) rhuMAbVEGF , which has synergy with chemotherapy in animal models . The present study was design ed to assess the safety and pharmacokinetics of weekly intravenous ( IV ) rhuMAbVEGF with one of three st and ard chemotherapy regimens . PATIENTS AND METHODS Twelve adult patients were enrolled four on each combination .  rhuMAbVEGF , 3 mg/kg IV , was administered weekly for 8 weeks with ( 1 ) doxorubicin 50 mg/m(2 ) every 4 weeks ; ( 2 ) carboplatin at area under the curve of 6 plus paclitaxel 175 mg/m(2 ) every 4 weeks ; and ( 3 ) fluorouracil ( 5-FU ) 500 mg/m(2 ) with leucovorin 20 mg/m(2 ) weekly , weeks 1 to 6 every 8 weeks . RESULTS The median number of rhuMAbVEGF  doses delivered was eight ( range , four to eight doses ) . Grade 3 toxicities were diarrhea ( one 5-FU patient ) , thrombocytopenia ( two patients on carboplatin plus paclitaxel ) , and leukopenia ( one patient on carboplatin plus paclitaxel ) . These toxicities were likely attributable to the chemotherapy component of the regimen . The mean ( + /- SD ) peak serum level of rhuMAbVEGF was 167 + /- 46 microg/mL , and the mean terminal half-life was 13 days . Total ( free plus bound ) serum VEGF levels increased from 51 + /- 39 pg/mL ( day 0 ) to 211 + /- 112 ( day 49 ) pg/mL. Three responding patients continued treatment with rhuMAbVEGF and chemotherapy , receiving the equivalent of 36 , 20 , and 40 total rhuMAbVEGF doses with no cumulative or late toxicities . CONCLUSION rhuMAbVEGF can be safely combined with chemotherapy at doses associated with VEGF blockade and without apparent synergistic toxicity . Its contribution to the treatment of advanced solid tumors should be evaluated in r and omized treatment trials On June 20 , 2006 , the U.S. Food and Drug Administration ( FDA ) approved bevacizumab ( Avastin ; Genentech , Inc. , South San Francisco , CA ) , administered in combination with FOLFOX4 ( 5-fluorouracil , leucovorin , and oxaliplatin ) for the second-line treatment of metastatic carcinoma of the colon or rectum . Efficacy and safety were demonstrated in one Eastern Cooperative Oncology Group ( ECOG ) open-label , multicenter , r and omized , three-arm , active-controlled trial enrolling 829 adult patients . Patients had received a  fluoropyrimidine- and irinotecan-based regimen as initial therapy for metastatic disease ; or they had received prior adjuvant irinotecan-based chemotherapy and had recurred within 6 months of completing therapy . Treatments included bevacizumab , 10 mg/kg , as a 90-minute i.v . infusion on day 1 , every 2 weeks , either alone or in combination with FOLFOX4 , or FOLFOX4 alone . The bevacizumab monotherapy arm was closed to accrual after an interim efficacy analysis suggested a possibly shorter survival in that arm . Overall survival ( OS ) , the primary study endpoint , was significantly longer for patients receiving  bevacizumab in combination with FOLFOX4 than for those receiving FOLFOX4 alone . The objective response rate was significantly higher in the FOLFOX4 plus bevacizumab arm than in the FOLFOX4 alone arm . The duration of response was approximately 6 months for both treatment arms . Patients treated with the bevacizumab combination were also reported , based on investigator assessment , to have significantly longer progression-free survival . There were no new bevacizumab  safety signals . The most serious , and sometimes fatal , bevacizumab toxicities are gastrointestinal perforation , wound-healing complications , hemorrhage , arterial thromboembolic events , hypertensive crisis , nephrotic syndrome , and congestive heart failure PURPOSE The National Surgical Adjuvant Breast and Bowel Project C-08 trial was design ed to investigate the safety and effectiveness of adding bevacizumab to modified infusional fluorouracil , leucovorin , and oxaliplatin ( FOLFOX ) 6 regimen for the adjuvant treatment of patients with stage II or III colon cancer . We present safety information in advance of the planned analysis of efficacy . PATIENTS AND METHODS Among 2,710 r and omly assigned patients , demographic factors were balanced . Patients received modified FOLFOX6 every 2 weeks x 12 or modified FOLFOX6 plus bevacizumab ( 5 mg/kg every 2 weeks x 26 , experimental group ) . RESULTS Overall rates of grade 4 or 5 toxicities were nearly identical in the FOLFOX6 and FOLFOX6 plus bevacizumab arms ( 15.2 % and 15.0 % , respectively ) . Six-month mortality rates were 0.96 % and 0.90 % for the control and experimental groups , respectively . Grade 3 + toxicities that occurred more often in the experimental arm versus control arm included hypertension ( 12 % v 1.8 % , respectively ) , wound complications ( abdominal incisional hernia or infusion port dehiscence/inflammation ; 1.7 % v 0.3 % , respectively ) , pain ( 11.1 % v 6.3 % , respectively ) , and proteinuria ( 2.7 % v 0.8 % , respectively ) . Grade 2 + neuropathy was increased in the experimental arm versus 
    Output:
    
Subgroup analyses stratified by CTX was also performed , evident benefits of additional  BEV in OS and PFS can be identified in all subgroups , except for the CTX containing capecitabine in OS .
Moreover , the increased rate of incidence was also identified in hypertension , thrombosis , proteinuria , gastrointestinal perforation , and fatigue .
BEV , acting as a targeted agent to CTX , its additional benefit to CTX is at the cost of increased toxicity