***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 When cure is impossible , cancer treatment should focus on both length and quality of life . Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals . The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim . Methods COIN was a r and omised controlled trial in patients with previously untreated advanced colorectal cancer . Patients received either continuous oxaliplatin and fluoropyrimidine combination ( arm A ) , continuous chemotherapy plus cetuximab ( arm B ) , or intermittent ( arm C ) chemotherapy . In arms A and B , treatment continued until development of progressive disease , cumulative toxic effects , or the patient chose to stop . In arm C , patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression , when the same treatment was restarted . 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 B is described in a companion paper . Here , we compare arms A and C , with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy , with a predefined non-inferiority boundary of 1·162 . Intention-to-treat ( ITT ) and per- protocol analyses were done . This trial is registered , IS RCT N27286448 . Findings 1630 patients were r and omly assigned to treatment groups ( 815 to continuous and 815 to intermittent therapy ) . Median survival in the ITT population ( n=815 in both groups ) was 15·8 months ( IQR 9·4–26·1 ) in arm A and 14·4 months ( 8·0–24·7 ) in arm C ( hazard ratio [ HR ] 1·084 , 80 % CI 1·008–1·165 ) . In the per- protocol population ( arm A , n=467 ; arm C , n=511 ) , median survival was 19·6 months ( 13·0–28·1 ) in arm A and 18·0 months ( 12·1–29·3 ) in arm C ( HR 1·087 , 0·986–1·198 ) . The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary . Preplanned subgroup analyses in the per- protocol population showed that a raised baseline platelet count , defined as 400 000 per μL or higher ( 271 [ 28 % ] of 978 patients ) , was associated with poor survival  with intermittent chemotherapy : the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 ( 95 % CI 0·80–1·15 , p=0·66 ) , versus 1·54 ( 1·17–2·03 , p=0·0018 ) in patients with a raised platelet count ( p=0·0027 for interaction ) . In the per- protocol population , more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects ( 72 [ 15 % ] vs 60 [ 12 % ] ) , whereas nausea and vomiting were more common on intermittent treatment ( 11 [ 2 % ] vs 43 [ 8 % ] ) . Grade 3 or worse peripheral neuropathy ( 126 [ 27 % ] vs 25 [ 5 % ] ) and h and –foot syndrome ( 21 [ 4 % ] vs 15 [ 3 % ] ) were more frequent on continuous than on intermittent treatment . Interpretation Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival , chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer , offering reduced time on chemotherapy , reduced cumulative toxic effects , and improved quality of life . Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival , whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break . Funding Cancer Research UK 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 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 
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We noted significant statistical heterogeneity in the overall survival analysis ( I2 = 51 % ) , likely due to the pooling of first-line and second-line studies .The addition of EGFR TKI to st and ard therapy in molecularly unselected participants did not show benefit in limited data sets ( meta- analysis not performed ) .
The addition of EGFR MAb to either chemotherapy or best supportive care improves progression-free survival ( moderate- to high- quality evidence ) , overall survival ( high- quality evidence ) , and tumour response rate ( moderate- to high- quality evidence ) , but may increase toxicity in people with KRAS exon 2 wild-type or extended RAS wild-type metastatic colorectal cancer ( moderate- quality evidence ) .
The addition of EGFR TKI to st and ard therapy does not improve clinical outcomes .
EGFR MAb combined with bevacizumab is of no clinical value ( very low- quality evidence ) .