***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 
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    Input: BACKGROUND Preliminary evidence suggests that magnesium wasting occurs in patients who are treated with epidermal-growth-factor receptor (EGFR)-targeting antibodies for colorectal cancer . The mechanism of this side-effect is unknown , and if all or a subset of patients are affected is also unclear . We aim ed to assess the incidence , characteristics , and predictive factors of magnesium wasting during treatment with EGFR-targeting antibodies , and to study the pathophysiology of this phenomenon . METHODS We measured prospect ively magnesium concentrations in a cohort of 98 patients with colorectal cancer treated with EGFR-targeting antibodies with or without combined chemotherapy .  The primary outcome measure was the slope of the serum magnesium concentrations over time . In 35 patients , 24-h urinary magnesium excretion was measured . In a subset of patients ( n=5 ) , an intravenous magnesium load test was done . 16 patients who had chemotherapy alone  acted as controls . A clinical protocol was written before initiation of the study , but because this was a non-interventional study , the protocol was not formally registered . FINDINGS 95 ( 97 % ) patients had decreasing serum magnesium concentrations during EGFR-targeting treatment compared with baseline measurements . The mean serum magnesium slope during EGFR-targeting treatment ( with or without combined chemotherapy ) was significantly lower compared with chemotherapy alone ( -0.00157 mmol/L/day , SD 0.00162 [ 95 % CI -0.00191 to -0.00123 ] vs 0.00014 mmol/L/day , SD -00076 [ -0.00026 to 0.00055 ] ; ( t test , p < 0.0001 ) . 24-h urine analysis and intravenous magnesium load tests showed a defect in renal magnesium reabsorption . INTERPRETATION EGFR-inhibiting antibodies compromised the renal magnesium retention capacity , leading to hypomagnesaemia in most patients . Future studies should address the effects of exposure and target affinity . Our study suggests a pivotal role of the EGFR-signalling pathway in regulating magnesium homoeostasis 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 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 ] . ) This r and omized phase II trial compared panitumumab plus fluorouracil , leucovorin , and irinotecan ( FOLFIRI ) with bevacizumab plus FOLFIRI as second‐line chemotherapy for wild‐type ( WT ) KRAS exon 2 metastatic colorectal cancer ( mCRC ) and to explore the values of oncogenes in circulating tumor DNA ( ctDNA ) and serum proteins as predictive biomarkers . Patients with WT KRAS exon 2 mCRC refractory to first‐line chemotherapy containing oxaliplatin and bevacizumab  were r and omly assigned to panitumumab plus FOLFIRI or bevacizumab plus FOLFIRI .  Of 121 r and omly assigned patients , 117 were eligible . Median overall survival ( OS ) for panitumumab plus FOLFIRI and bevacizumab plus FOLFIRI were 16.2 and 13.4 months [ hazard ratio ( HR ) , 1.16 ; 95 % CI , 0.76–1.77 ] , respectively . Progression‐free survival ( PFS ) was also similar ( HR , 1.14 ; 95 % CI , 0.78–1.66 ) . KRAS , NRAS , and BRAF status using ctDNA was successfully examined in 109 patients , and mutations were identified in 19 patients ( 17.4 % ) . Panitumumab plus FOLFIRI showed favorable survival compared with bevacizumab plus FOLFIRI in WT patients and unfavorable survival in those with mutations ( P for interaction = 0.026 in OS and 0.054 in PFS ) . OS with bevacizumab plus FOLFIRI was better than panitumumab plus FOLFIRI in patients with high serum vascular endothelial growth factor‐A ( VEGF‐A ) levels and worse in those with low levels ( P for interaction = 0.016 ) . Second‐line FOLFIRI plus panitumumab and FOLFIRI plus bevacizumab showed a similar efficacy in patients with WT KRAS exon 2 mCRC .  RAS and BRAF mutation in ctDNA could be a negative predictive marker for panitumumab BACKGROUND The OPUS study demonstrated that addition of cetuximab to 5-fluorouracil , folinic acid and oxaliplatin ( FOLFOX4 ) significantly improved objective response and progression-free survival ( PFS ) in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer ( mCRC ) . In patients with KRAS exon 2 mutations , a detrimental effect was seen upon addition of cetuximab to FOLFOX4 . The current study reports outcomes in subgroups defined by extended RAS testing . PATIENTS AND METHODS Sample s from OPUS study KRAS exon 2 wild-type tumours were reanalysed for other RAS mutations in four additional KRAS codons ( exons 3 - 4 ) and six NRAS codons ( exons 2 - 4 ) using BEAMing . A cutoff of ⩾5 % mutant/wild-type sequences was selected to define RAS status ; we also report an analysis using a cutoff based on the technical lower limit for mutation identification ( 0.1 % ) . RESULTS Other RAS mutations were detected in 31/118 ( 26 % ) evaluable patients . In the extended analysis of RAS wild-type tumours ( n=87 ) , objective response was significantly improved by addition of cetuximab to FOLFOX4 ( 58 % versus 29 % ; odds ratio 3.33 [ 95 % confidence interval 1.36 - 8.17 ] ; P=0.0084 ) ; although limited by population size , there also appeared to be trends favouring the cetuximab arm in terms of PFS and overall survival in the RAS wild-type group compared with the RAS evaluable group . There was no evidence that patients with other RAS mutations benefited from cetuximab , but small numbers precluded precise estimations of treatment effects . In the combined population of patients with any RAS mutation ( KRAS exon 2 or other RAS ) , a clear detrimental effect was associated with addition of cetuximab to FOLFOX4 . CONCLUSION Patients with RAS-mutant mCRC , as defined by mutations in KRAS and NRAS exons 2 - 4 , derive no benefit and may be harmed by the addition of cetuximab to FOLFOX4 . Restricting cetuximab administration to patients with RAS wild-type tumours will further tailor therapy to maximise benefit Summary Background Thera 
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Conclusions : In conclusion , this meta- analysis shows that cetuximab- and panitumumab-based chemotherapy have different toxicity profiles in terms of the rate of severe adverse events