***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: 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 BACKGROUND Cetuximab , an IgG1 chimeric monoclonal antibody against epidermal growth factor receptor ( EGFR ) , has activity against colorectal cancers that express EGFR . METHODS From December 2003 to August 2005 , 572 patients who had colorectal cancer expressing immunohistochemically detectable EGFR and who had been previously treated with a fluoropyrimidine , irinotecan , and oxaliplatin or had contraindications to treatment with these drugs underwent r and omization to an initial dose of 400 mg of cetuximab per square meter of body-surface area followed by a weekly infusion of 250 mg per square meter plus best supportive care  ( 287 patients ) or best supportive care alone  ( 285 patients ) . The primary end point was overall survival . RESULTS In comparison with best supportive care alone , cetuximab treatment was associated with a significant improvement in overall survival ( hazard ratio for death , 0.77 ; 95 % confidence interval [ CI ] , 0.64 to 0.92 ; P=0.005 ) and in progression-free survival ( hazard ratio for disease progression or death , 0.68 ; 95 % CI , 0.57 to 0.80 ; P<0.001 ) . These benefits were robust after adjustment in a multivariable Cox proportional-hazards model . The median overall survival was 6.1 months in the cetuximab group and 4.6 months in the group assigned to supportive care alone . Partial responses occurred in 23 patients ( 8.0 % ) in the cetuximab group but in none in the group assigned to supportive care alone ( P<0.001 ) ; the disease was stable in an additional 31.4 % of patients assigned to cetuximab and in 10.9 % of patients assigned to supportive care alone ( P<0.001 ) . Quality of life was better preserved in the cetuximab group , with less deterioration in physical function and global health status scores ( both P<0.05 ) . Cetuximab treatment was associated with a characteristic rash ; a rash of grade 2 or higher was strongly associated with improved survival ( hazard ratio for death , 0.33 ; 95 % CI , 0.22 to 0.50 ; P<0.001 ) . The incidence of any adverse event of grade 3 or higher was 78.5 % in the cetuximab group and 59.1 % in the group assigned to supportive care alone ( P<0.001 ) . CONCLUSIONS Cetuximab improves overall survival and progression-free survival and preserves quality -of-life measures in patients with colorectal cancer in whom other treatments have failed . ( Clinical Trials.gov number , NCT00079066 [ Clinical Trials.gov ] . ) BACKGROUND the interplay between comorbidity , age and performance status ( PS ) as predictors of outcome in advanced colorectal cancer ( ACRC ) is poorly understood . We examined these factors as predictors of treatment toxicity and outcome in  cetuximab-treated patients with ACRC . PATIENTS AND METHODS comorbidity was independently evaluated using the Charlson Comorbidity Index ( CCI ) , a vali date d measure of comorbidity based on the presence of medical conditions weighted according to their effect on mortality . CCI score was correlated with clinical and outcome data . RESULTS five hundred and seventy-two patients were included ; 41 % were ≥ 65 years and 25 % had comorbidities at r and omization . In multivariate analysis ( MVA ) of all covariates , only older age was associated with greater comorbidity ( P = 0.008 ) . Overall survival ( OS ) was significantly better for patients with greater comorbidity in univariate analysis ( P = 0.047 ) . Conversely , better PS was associated with better OS in MVA ( hazard ratio 1.92 for PS = 2 versus PS = 0 , P < 0.0001 ) . Age was not associated with OS ( P = 0.13 ) . Elderly patients had significantly less grade ≥ 3 vomiting ( P = 0.034 ) but more dyspnea ( P = 0.005 ) . Patients with greater comorbidity had significantly less grade ≥ 3 vomiting ( P = 0.002 ) but more non-neutropenic fever ( P = 0.005 ) . CONCLUSION better PS was associated with improved OS . For patients with good PS , restricting cetuximab use in the setting of significant comorbidity does not appear justified BACKGROUND Elderly patients are underrepresented in chemotherapy trials for advanced colorectal cancer ( CRC ) and non-small-cell lung cancer ( NSCLC ) . However , the change in underrepresentation over time has not been documented . AIMS This study aim ed to quantify ( i ) the change in the  median age of patients enrolled in clinical trials for metastatic CRC and NSCLC between 1982 - 1991 and 1992 - 2001 compared with the general colorectal and lung cancer population , and ( ii ) the proportion of trials with an upper age limit for eligibility . METHODS A retrospective review of data from the Victorian Cancer Registry and all large published r and omized chemotherapy trials for advanced CRC and NSCLC between 1982 and 2001 was conducted . RESULTS The median age of patients with CRC enrolled in clinical trials remained constant between the two decades ( 62.0 and 62.2 years ) , whereas the median age of the CRC population increased from 68.4 to 70.2 years , increasing the median age difference from 6.4 to 8.0 years . The median age of patients with lung cancer in clinical trials  increased from 59.8 to 61.8 years , whereas the median age of the lung cancer population  increased from 67.4 to 70.4 years , widening the age difference from 7.6 to 8.6 years . More trials set an upper age limit for eligibility in the first decade than in the second decade for both CRC ( 51 vs 29 % , P = 0.04 ) and NSCLC ( 68 vs 41 % , P = 0.03 ) . CONCLUSION International clinical trials for CRC and NSCLC are becoming increasingly unsuitable for application to Australian patients because of the increasing age discrepancy , despite fewer trials restricting eligibility by age Summary Purpose To assess safety and efficacy of folinic acid , 5-fluorouracil , gemcitabine ( FFG ) and folinic acid , fluorouracil , oxaliplatin ( FOLFOX4 ) regimens with added bevacizumab as first-line treatment in patients with advanced colorectal cancer ( CRC ) . Patients and Methods Patients with Stage III unresectable or Stage IV adenocarcinoma of the colon or rectum were r and omly assigned to either FFG weekly for 6 weeks of an 8-week cycle or FOLFOX4 every 2 weeks . After FDA approval , bevacizumab 5 mg/kg was added every 2 weeks . Treatment continued until disease progression . Planned enrollment was 190 patients . Primary endpoint was overall response rate ( ORR ) ; secondary endpoints included evaluation of adverse events , time to progression ( TTP ) , and overall survival ( OS ) . Disease Control Rate ( DCR ; % of patients with complete or partial responses or stable disease ) was a post hoc analysis . Results The trial was stopped prematurely due to low enrollment . Of 84 enrolled patients ( 42 to each arm ) , 36 patients ( 18 in each arm ) received  bevacizumab .  ORR was greater ( P = .002 ) for FOLFOX4 ( 17/42 ; 40.5 % ) than for FFG ( 4/42 ; 9.5 % ) ; however , TTP , OS , and DCR results were not statistically different comparing FOLFOX4 and FFG . Peripheral neuropathy was more frequent ( P = < .001 ) with FOLFOX4 ( 18/42 ; 42.9 % ) than with FFG ( 1/42 ; 2.4 % ) . Conclusions FFG and FOLFOX4 were generally well tolerated . Based on ORR , FOLFOX4 was superior to FFG . However , differences in TTP and OS comparing regimens were inconclusive . General use of gemcitabine as a biomodulator of 5-fluorouracil in CRC can not be recommended at this time and the regimen remains investigational 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 Summary Background Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer , but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain . Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer . Methods In this open-label , r and omised trial , we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK . From December , 2006 until June , 2008 , molecularly unselected patients were recruited to a three-arm design including irinotecan ( control ) , irinotecan plus ciclosporin , and irinotecan plus panitumumab ( IrPan ) groups . From June 10 , 2008 , in response to new data , the trial was amended to a prospect ively stratified design , restricting panitumumab r and omisation to patients with KRAS wild-type tumours ; the results of the comparison between the irinotcan and IrPan groups are reported here . We used a computer-generated r and omisation sequence ( stratified by previous EGFR targeted therapy and then minimised by centre , WHO performance status , previous oxaliplatin , previous bevacizumab , previous dose modifications , and best 
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Elderly/frail patients are underrepresented in RCTs study ing targeted therapies in mCRC , and those elderly patients included in RCTs do not reflect well the general elderly population with mCRC because of the exclusion criteria .
RCTs results concerning targeted therapies can be inferred only to relatively healthy elderly subjects