***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: 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 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 , 0.95 ; 95 % CI , 0.82 to 1.10 ; P = .541 ) , or overall response rate ( 46.3 % v 47.3 % ) . Median PFS and OS were 9.9 and 22.8 months for mFOLFOX6/cediranib and 10.3 and 21.3 months for mFOLFOX6/bevacizumab . The PFS upper 95 % CI was outside the predefined noninferiority limit ( HR < 1.2 ) . Common adverse events with more than 5 % incidence in the cediranib arm included diarrhea , neutropenia , and hypertension .  Cediranib-treated patients completed fewer chemotherapy cycles than bevacizumab-treated patients ( median 10 v 12 cycles ) . Patient-reported outcomes ( PROs ) were significantly less favorable in cediranib-treated versus bevacizumab-treated patients ( P < .001 ) . CONCLUSION Cediranib activity , in terms of PFS and OS , was comparable to that of bevacizumab when added to mFOLFOX6 ; however , the predefined boundary for PFS noninferiority was not met . The cediranib  safety profile was consistent with previous studies but led to less favorable PROs compared with bevacizumab . Investigation of oral TKIs in CRC continues 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 optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined . Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer . METHODS In this open-label , r and omised , phase 3 trial , we r and omly assigned patients ( 1:1 ratio ) with advanced , measurable , non-resectable colorectal cancer and WHO performance status 0 - 2 to receive either first-line treatment with bolus ( 400 mg/m(2 ) ) and infusional ( 2400 mg/m(2 ) ) fluorouracil plus leucovorin ( 400 mg/m(2 ) ) ( simplified LV5FU2 regimen ) , second-line LV5FU2 plus oxaliplatin ( 100 mg/m(2 ) ) ( FOLFOX6 ) , and third-line LV5FU2 plus irinotecan ( 180 mg/m(2 ) ) ( FOLFIRI ) or first-line FOLFOX6 and second-line FOLFIRI . Chemotherapy was administered every 2 weeks . R and omisation was done central ly using minimisation ( minimisation factors were WHO performance status , previous adjuvant chemotherapy , number of disease sites , and centre ) . The primary endpoint was progression-free survival after two lines of treatment . Analyses were by intention-to-treat . This trial is registered at Clinical Trials.gov , NCT00126256 . FINDINGS 205 patients were r and omly assigned to the sequential group and 205 to the combination group . 161 ( 79 % ) patients in the sequential group and 161 ( 79 % ) in the combination group died during the study . Median progression-free survival after two lines was 10·5 months ( 95 % CI 9·6 - 11·5 ) in the sequential group and 10·3 months ( 9·0 - 11·9 ) in the combination group ( hazard ratio 0·95 , 95 % CI 0·77 - 1·16 ; p=0·61 ) . All six deaths caused by toxic effects of treatment occurred in the combination group . During first-line chemotherapy , significantly fewer severe ( grade 3 - 4 ) haematological adverse events ( 12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group ; p<0·0001 ) and non-haematological adverse events ( 26 events vs 186 events ; p<0·0001 ) occurred in the sequential group than in the combination group . INTERPRETATION Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced , non-resectable colorectal cancer . FUNDING Sanofi-Aventis France PURPOSE To determine whether irinotecan plus oxaliplatin ( mIROX ) is superior to irinotec 
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RESULTS Analysis of 33 trials reporting treatment effects on all three outcomes showed reasonably strong association between treatment effects on PFS and OS , however the association parameters were obtained with a large uncertainty .
A weak surrogate relationship was noted between the treatment effects on TR and OS .
Modelling the two surrogate endpoints , TR and PFS , jointly as predictors of treatment effect on OS gave no marked improvement to surrogate association patterns .
Modest improvement in the precision of the predicted treatment effects on the final outcome was noted in studies investigating anti-angiogenic therapy , however it was likely due to chance .
The joint use of two surrogate endpoints did not lead to marked improvement in the association between treatment effects on surrogate and final endpoints in advanced colorectal cancer