***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: We present the preliminary toxicity data from the MRC COIN trial , a phase III r and omised controlled trial of first-line therapy in advanced colorectal cancer , with particular reference to the addition of cetuximab to an oxaliplatin – fluoropyrimidine combination .  A total of 804 patients were r and omised between March 2005 and July 2006 from 78 centres throughout the United Kingdom . Patients were allocated to oxaliplatin plus fluoropyrimidine chemotherapy with or without the addition of weekly cetuximab . The choice of fluoropyrimidine ( either 5-fluorouracil ( 5FU ) or capecitabine ) was decided by the treating physician and patient before r and omisation . Toxicity data were collected from all patients . Two hundred and three patients received 5FU plus oxaliplatin ( OxMdG , 25 % ) , 333 oxaliplatin+capecitabine ( Xelox , 41 % ) , 102 received OxMdG+cetuximab ( OxMdG+C , 13 % ) and 166 Xelox+cetuximab ( 21 % ) . Percent grade 3/4 toxicities included diarrhoea 6 , 15 , 13 and 25 % , nausea/vomiting 3 , 7 , 7 and 14 % for OxMdG , Xelox , OxMdG+C and Xelox+C , respectively . Sixty-day all-cause mortality was 6 , 5 , 5 and 7 % . Statistically significant differences were evident for patients receiving Xelox+cetuximab vs Xelox alone : diarrhoea relative risk ( RR ) 1.69 ( 1.17 , 2.43 , P=0.005 ) and nausea/vomiting RR 2.01 ( 1.16 , 3.47 , P=0.012 ) . The excess toxicity observed in the oxaliplatin- , capecitabine- , cetuximab-treated patients led the trial management group to conclude that a capecitabine dose adjustment was required to maintain safety levels when using this regimen BACKGROUND Targeting the vascular endothelial growth factor or the epidermal growth factor receptor ( EGFR ) has shown efficacy in advanced colorectal cancer ( ACC ) , but no data are available on the combination of these strategies with chemotherapy in the first-line treatment . The CAIRO2 study evaluates the effect of adding cetuximab , a chimeric mAb against EGFR , to capecitabine , oxaliplatin and bevacizumab in the first-line treatment of ACC . PATIENTS AND METHODS In all , 755 patients were r and omly assigned between treatment with capecitabine , oxaliplatin and bevacizumab with or without cetuximab . The primary end point is progression-free survival . We here present the toxicity results in the first 400 patients that entered the study . RESULTS The incidence of overall grade 3 - 4 toxicity was significantly higher in arm B compared with arm A ( 81 % versus 72 % , P = 0.03 ) . This difference is fully attributed to cetuximab-related skin toxicity . The addition of cetuximab did not result in an increase of gastrointestinal toxicity or treatment-related mortality . CONCLUSIONS The addition of cetuximab to capecitabine , oxaliplatin and bevacizumab in the first-line treatment of ACC appears to be safe and feasible . No excessive or unexpected toxicity in the cetuximab-containing treatment arm was observed Summary Background In the Medical Research Council ( MRC ) COIN trial , the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to st and ard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival . Methods In this r and omised controlled trial , patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were r and omly assigned to oxaliplatin and fluoropyrimidine chemotherapy ( arm A ) , the same combination plus cetuximab ( arm B ) , or intermittent chemotherapy ( arm C ) . The choice of fluoropyrimidine therapy ( capecitabine or infused fluouroracil plus leucovorin ) was decided before r and omisation . R and omisation was done central ly ( via telephone ) by the MRC Clinical Trials Unit using minimisation . Treatment allocation was not masked . The comparison of arms A and C is described in a companion paper . Here , we present the comparison of arm A and B , for which the primary outcome was overall survival in patients with KRAS wild-type tumours . Analysis was by intention to treat . Further analyses with respect to NRAS , BRAF , and EGFR status were done . The trial is registered , IS RCT N27286448 . Findings 1630 patients were r and omly assigned to treatment groups ( 815 to st and ard therapy and 815 to addition of cetuximab ) . Tumour sample s from 1316 ( 81 % ) patients were used for somatic molecular analyses ; 565 ( 43 % ) had KRAS mutations . In patients with KRAS wild-type tumours ( arm A , n=367 ; arm B , n=362 ) , overall survival did not differ between treatment groups ( median survival 17·9 months [ IQR 10·3–29·2 ] in the control group vs 17·0 months [ 9·4–30·1 ] in the cetuximab group ; HR 1·04 , 95 % CI 0·87–1·23 , p=0·67 ) . Similarly , there was no effect on progression-free survival ( 8·6 months [ IQR 5·0–12·5 ] in the control group vs 8·6 months [ 5·1–13·8 ] in the cetuximab group ; HR 0·96 , 0·82–1·12 , p=0·60 ) . Overall response rate increased from 57 % ( n=209 ) with chemotherapy alone to 64 % ( n=232 ) with addition of cetuximab ( p=0·049 ) . Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab ( 14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours , respectively ) . Overall survival differs by somatic mutation status irrespective of treatment received : BRAF mutant , 8·8 months ( IQR 4·5–27·4 ) ; KRAS mutant , 14·4 months ( 8·5–24·0 ) ; all wild-type , 20·1 months ( 11·5–31·7 ) . Interpretation This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer .  Cetuximab  increases response rate , with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours . The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases can not be recommended . Funding Cancer Research UK , Cancer Research Wales , UK Medical Research Council , Merck BACKGROUND Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics : both tumour shrinkage ( objective response ) and disease progression are useful endpoints in clinical trials . Since RECIST was published in 2000 , many investigators , cooperative groups , industry and government authorities have adopted these criteria in the assessment of treatment outcomes . However , a number of questions and issues have arisen which have led to the development of a revised RECIST guideline ( version 1.1 ) . Evidence for changes , summarised in separate papers in this special issue , has come from assessment of a large data warehouse ( > 6500 patients ) , simulation studies and literature review s. HIGHLIGHTS OF REVISED RECIST 1.1 : Major changes include : Number of lesions to be assessed : based on evidence from numerous trial data bases merged into a data warehouse for analysis purpose s , the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total ( and from five to two per organ , maximum ) . Assessment of pathological lymph nodes is now incorporated : nodes with a short axis of 15 mm are considered measurable and assessable as target lesions . The short axis measurement should be included in the sum of lesions in calculation of tumour response . Nodes that shrink to < 10 mm short axis are considered normal . Confirmation of response is required for trials with response primary endpoint but is no longer required in r and omised studies since the control arm serves as appropriate means of interpretation of data . Disease progression is clarified in several aspects : in addition to the previous definition of progression in target disease of 20 % increase in sum , a 5 mm absolute increase is now required as well to guard against over calling PD when the total sum is very small . Furthermore , there is guidance offered on what constitutes ' unequivocal progression ' of non-measurable/non-target disease , a source of confusion in the original RECIST guideline . Finally , a section on detection of new lesions , including the interpretation of FDG-PET scan assessment is included . Imaging guidance : the revised RECIST includes a new imaging appendix with up date d recommendations on the optimal anatomical assessment of lesions . FUTURE WORK A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI . It was concluded that , at present , there is not sufficient st and ardisation or evidence to ab and on anatomical assessment of tumour burden . The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression . As is detailed in the final paper in this special issue , the use of these promising newer approaches requires appropriate clinical validation studies BACKGROUND The growing availability of active agents makes the development of novel therapies increasingly complex and the choice of end points critical . We assessed the frequency of use of efficacy end points in advanced breast cancer . METHODS We search ed PubMed for r and omized trials published between 2000 and 2007 in 10 leading medical journals . We abstract ed data on  progression-free survival ( PFS ) , time to tumor progression ( TTP ) , response rate ( RR ) and overall survival .  RESULTS A total of 58 studies enrolled 23,371 assessable patients in 122 treatment arms . The primary end points most frequently used were RR and TTP ( n=21 each ) , followed by PFS ( n=14 ) . In five of the trials using TTP as the primary end point , no definition of TTP was reported ; in 13 of the other 16 cases , death was counted as an event , making TTP indistinguishable from PFS . Trials having PFS , TTP or time to treatment failure as the primary end point ( n=36 ) had a higher mean number of patients than those using RR ( P=0.061 ) . CONCLUSION Investigators seem to be frequently using PFS and TTP interchangeably in advanced breast cancer . Such use of terms may lead to confusion when results of different trials are compared , and uniform use of definitions seems in order PURPOSE To compare the efficacy of cediranib ( a vascular endothelial growth factor receptor tyrosine kinase inhibitor [ VEGFR TKI ] ) with that of bevacizumab ( anti-VEGF-A monoclonal antibody ) in combination with chemotherapy as first-line treatment for advanced metastatic colorectal cancer ( mCRC ) . PATIENTS AND METHODS HORIZON III [ Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer ] had an adaptive phase II/III design . Patients r and omly assigned 1:1:1 received mFOLFOX6 [ oxaliplatin 85 mg/m(2 ) and leucovorin 400 mg/m(2 ) intravenously followed by fluorouracil 400 mg/m(2 ) intravenously on day 1 and then continuous infusion of 2,400 mg/m(2 ) over the next 46 hours every 2 weeks ] with cediranib ( 20 or 30 mg per day ) or bevacizumab ( 5 mg/kg every 14 days ) . An independent end-of-phase II analysis concluded that mFOLFOX6/cediranib 20 mg met predefined criteria for continuation ; subsequent patients received mFOLFOX6/cediranib 20 mg or mFOLFOX6/bevacizumab ( r and omly assigned 1:1 ) . The primary objective was to compare progression-free survival ( PFS ) . RESULTS In all , 1,422 patients received mFOLFOX6/cediranib  20 mg ( n = 709 ) or mFOLFOX6/bevacizumab ( n = 713 ) . Primary analysis revealed no significant difference between arms for PFS ( hazard ratio [ HR ] , 1.10 ; 95 % CI , 0.97 to 1.25 ; P = .119 ) , overall survival ( OS ; HR , 0.9 
    Output:
    
The addition of MA to CT for patients with metastatic colorectal cancer does not prolong GS and PFS