***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 Bevacizumab ( Avastin ; Genentech , South San Francisco , CA ) is a recombinant , humanized anti-vascular endothelial growth factor monoclonal antibody . Erlotinib HCl ( Tarceva , OSI-774 ; OSI Pharmaceuticals , New York , NY ) is a potent , reversible , highly selective and orally available HER-1/epidermal growth factor receptor tyrosine kinase inhibitor . Pre clinical data in various xenograft models produced greater growth inhibition than with either agent alone . Additionally , both agents have demonstrated benefit in patients with previously treated non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS A phase I/II study in two centers examined erlotinib and bevacizumab ( A+T ) in patients with nonsquamous stage IIIB/IV NSCLC with > or = one prior chemotherapy .  In phase I , erlotinib 150 mg/day orally plus bevacizumab 15 mg/kg intravenously every 21 days was established as the phase II dose , although no dose-limiting toxicities were observed . Phase II assessed the efficacy and tolerability of A+T at this dose . Pharmacokinetic parameters were evaluated . Results Forty patients were enrolled and treated in this study ( 34 patients at phase II dose ) ; the median age was 59 years ( range , 36 to 72 years ) , 21 were female , 30 had adenocarcinoma histology , nine were never-smokers , and 22 had > or = two prior regimens ( three patients had > or = four prior regimens ) . The most common adverse events were mild to moderate rash , diarrhea , and proteinuria . Preliminary data showed no pharmacokinetic interaction between A + T. Eight patients ( 20.0 % ; 95 % CI , 7.6 % to 32.4 % ) had partial responses and 26 ( 65.0 % ; 95 % CI , 50.2 % to 79.8 % ) had stable disease as their best response . The median overall survival for the 34 patients treated at the phase II dose was 12.6 months , with progression-free survival of 6.2 months . CONCLUSION Encouraging antitumor activity and safety of A + T support further development of this combination for patients with advanced NSCLC and other solid tumors BACKGROUND Treatment with cetuximab , a monoclonal antibody directed against the epidermal growth factor receptor , improves overall and progression-free survival and preserves the quality of life in patients with colorectal cancer that has not responded to chemotherapy . The mutation status of the K-ras gene in the tumor may affect the response to cetuximab and have treatment-independent prognostic value . METHODS We analyzed tumor sample s , obtained from 394 of 572 patients ( 68.9 % ) with colorectal cancer who were r and omly assigned to receive cetuximab plus best supportive care or best supportive care alone  , to look for activating mutations in exon 2 of the K-ras gene . We assessed whether the mutation status of the K-ras gene was associated with survival in the cetuximab and supportive-care groups . RESULTS Of the tumors evaluated for K-ras mutations , 42.3 % had at least one mutation in exon 2 of the gene . The effectiveness of cetuximab was significantly associated with K-ras mutation status ( P=0.01 and P<0.001 for the interaction of K-ras mutation status with overall survival and progression-free survival , respectively ) . In patients with wild-type K-ras tumors , treatment with cetuximab as compared with supportive care alone significantly improved overall survival ( median , 9.5 vs. 4.8 months ; hazard ratio for death , 0.55 ; 95 % confidence interval [ CI ] , 0.41 to 0.74 ; P<0.001 ) and progression-free survival ( median , 3.7 months vs. 1.9 months ; hazard ratio for progression or death , 0.40 ; 95 % CI , 0.30 to 0.54 ; P<0.001 ) . Among patients with mutated K-ras tumors , there was no significant difference between those who were treated with cetuximab and those who received supportive care alone with respect to overall survival ( hazard ratio , 0.98 ; P=0.89 ) or progression-free survival ( hazard ratio , 0.99 ; P=0.96 ) . In the group of patients receiving best supportive care alone , the mutation status of the K-ras gene was not significantly associated with overall survival ( hazard ratio for death , 1.01 ; P=0.97 ) . CONCLUSIONS Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab , whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab . The mutation status of the K-ras gene had no influence on survival among patients treated with best supportive care alone . ( Clinical Trials.gov number , NCT00079066 . Objective To evaluate the reliability of risk of bias assessment s based on published trial reports , for determining trial inclusion in meta-analyses . Design Reliability evaluation of risk of bias assessment s. Data sources 13 published individual participant data ( IPD ) meta-analyses in cancer were used to source 95 r and omised controlled trials . Review methods Risk of bias was assessed using the Cochrane risk of bias tool ( RevMan5.1 ) and accompanying guidance . Assessment s were made for individual risk of bias domains and overall for each trial , using information from either trial reports alone or trial reports with additional information collected for IPD meta-analyses . Percentage agreements were calculated for individual domains and overall ( < 66%=low , ≥66%=fair , ≥90%=good ) . The two approaches were considered similarly reliable only when agreement was good . Results Percentage agreement between the two methods for sequence generation and incomplete outcome data was fair ( 69.5 % ( 95 % confidence interval 60.2 % to 78.7 % ) and 80.0 % ( 72.0 % to 88.0 % ) , respectively ) . However , percentage agreement was low for allocation concealment , selective outcome reporting , and overall risk of bias ( 48.4 % ( 38.4 % to 58.5 % ) , 42.1 % ( 32.2 % to 52.0 % ) , and 54.7 % ( 44.7 % to 64.7 % ) , respectively ) . Supplementary information reduced the proportion of unclear assessment s for all individual domains , consequently increasing the number of trials assessed as low risk of bias ( and therefore available for inclusion in meta-analyses ) from 23 ( 23 % ) based on publications alone to 66 ( 66 % ) based on publications with additional information . Conclusions Using cancer trial publications alone to assess risk of bias could be unreliable ; thus , review ers should be cautious about using them as a basis for trial inclusion , particularly for those trials assessed as unclear risk . Supplementary information from trialists should be sought to enable appropriate assessment s and potentially reduce or overcome some risks of bias . Furthermore , guidance should ensure clarity on what constitutes risk of bias , particularly for the more subjective domains PURPOSE We evaluated the safety and efficacy of concurrent administration of two monoclonal antibodies , cetuximab and bevacizumab , in patients with metastatic colorectal cancer . PATIENTS AND METHODS This was a r and omized phase II study in patients with irinotecan-refractory colorectal cancer . All patients were naïve to both bevacizumab and cetuximab .  Patients in arm A received irinotecan at the same dose and schedule as last received before study entry , plus cetuximab 400 mg/m2 loading dose , then weekly cetuximab 250 mg/m2 , plus bevacizumab 5 mg/kg administered every other week . Patients in arm B received the same cetuximab and bevacizumab as those in arm A but without irinotecan . RESULTS Forty-three patients received cetuximab , bevacizumab , and irinotecan ( CBI ) and 40 patients received cetuximab and bevacizumab  alone ( CB ) . Toxicities were as would have been expected from the single agents . For the CBI arm , time to tumor progression ( TTP ) was 7.3 months and the response rate was 37 % ; for the CB arm , TTP was 4.9 months and the response rate was 20 % . The overall survival for the CBI arm was 14.5 months and the overall survival for the CB-alone arm was 11.4 months . CONCLUSION Cetuximab and bevacizumab can be administered concurrently , with a toxicity pattern that seems to be similar to that which would be expected from the two agents alone . This combination plus irinotecan also seems to be feasible . The activity seen with the addition of bevacizumab to cetuximab , or to cetuximab plus irinotecan , seems to be favorable when compared with historical controls of cetuximab or cetuximab/irinotecan in patients who are naïve to bevacizumab PURPOSE To assess the feasibility of administering OSI-774 , to recommend a dose on a protracted , continuous daily schedule , to characterize its pharmacokinetic behavior , and to acquire preliminary evidence of anticancer activity . PATIENTS AND METHODS Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts ( A to C ) to evaluate progressively longer treatment intervals . Part A patients received OSI-774 25 to 100 mg once daily , for 3 days each week , for 3 weeks every 4 weeks . Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose ( MTD ) . In part C , patients received this MTD on a continuous , uninterrupted schedule . The pharmacokinetics of OSI-774 and its O-demethylated metabolite , OSI-420 , were characterized . RESULTS Forty patients received a total of 123 28-day courses of OSI-774 .  No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B , the incidence of severe diarrhea and /or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d . Uninterrupted , daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule . The pharmacokinetics of OSI-774 were dose independent ; repetitive daily treatment did not result in drug accumulation ( at 150 mg/d [ average ] : minimum steady-state plasma concentration , 1.20 + /- 0.62 microg/mL ; clearance rate , 6.33 + /- 6.41 L/h ; elimination half-life , 24.4 + /- 14.6 hours ; volume of distribution , 136 . 4 + /- 93.1 L ; area under the plasma concentration-time curve for OSI-420 relative to OSI-774 , 0.12 + /- 0.12 microg/h/mL ) . CONCLUSION The recommended dose for disease-directed studies of OSI-774 administered orally on a daily , continuous , uninterrupted schedule is 150 mg/d . OSI-774 was well tolerated , and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease . The precise contribution of OSI-774 to these effects is not known RATIONALE This phase I study was conducted to determine the maximum tolerated dose ( MTD ) of erlotinib , an oral epidermal growth factor receptor tyrosine kinase inhibitor , with 5-fluorouracil/leucovorin/oxaliplatin ( FOLFOX4 ) in patients with advanced colorectal cancer ( CRC ) .  Bevacizumab was later included as st and ard of care at the MTD . PATIENTS AND METHODS Patients received FOLFOX4 with escalating doses of erlotinib : dose level ( DL ) 1 , 50 mg ; DL 2 , 100 mg ; and DL 3 , 150 mg once daily continuously . Bevacizumab 5 mg/kg days 1 and 15 was added at the MTD upon Food and Drug Administration approval . Correlative studies included pharmacokinetics , pharmacodynamics was assessed in paired skin biopsies , and fluorodeoxyglucose positron emission tomography scans . RESULTS Fifteen patients received 60 cycles ( 120 FOLFOX treatments ) . Two dose-limiting toxicities ( DLTs ) were seen at DL 3 : intolerable grade 2 rash ( Common Terminology Criteria for Adverse Events version 2 ) lasting > 1 week , and grade 4 neutropenia . Dose level 2 was exp and ed to 6 more patients , this time adding bevacizumab , and 1 DLT of grade 3 mucositis occurred . As expected , the primary toxicities were cytopenias , diarrhea , rash , and fatigue . There were 2 occurrences of pneumatosis . One patient experienced an unrelated grade 4 myocardial infa 
    Output:
    
The side effects of diarrhea and grade III rash were more frequent in the group administered bevacizumab plus erlotinib .
The combination of bevacizumab and erlotinib , in the maintenance treatment of metastatic colorectal cancer , significantly improved the overall survival and progression-free survival of patients , and the result ing side effects were easily treatable