***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: PURPOSE In metastatic colorectal cancer , phase III studies have demonstrated the superiority of fluorouracil ( FU ) with leucovorin ( LV ) in combination with irinotecan or oxaliplatin over FU + LV alone . This phase III study investigated two sequences : folinic acid , FU , and irinotecan ( FOLFIRI ) followed by folinic acid , FU , and oxaliplatin ( FOLFOX6 ; arm A ) , and FOLFOX6 followed by FOLFIRI ( arm B ) . PATIENTS AND METHODS Previously untreated patients with assessable disease were r and omly assigned to receive a 2-hour infusion of l-LV 200 mg/m(2 ) or dl-LV 400 mg/m(2 ) followed by a FU bolus 400 mg/m(2 ) and 46-hour infusion 2,400 to 3,000 mg/m(2 ) every 46 hours every 2 weeks , either with irinotecan 180 mg/m(2 ) or with oxaliplatin 100 mg/m(2 ) as a 2-hour infusion on day 1 . At progression , irinotecan was replaced by oxaliplatin ( arm A ) , or oxaliplatin by irinotecan ( arm B ) . RESULT Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI ( P = .99 ) . Median second progression-free survival ( PFS ) was 14.2 months in arm A versus 10.9 in arm B ( P = .64 ) . In first-line therapy , FOLFIRI achieved 56 % response rate ( RR ) and 8.5 months median PFS , versus FOLFOX6 which achieved 54 % RR and 8.0 months median PFS ( P = .26 ) . Second-line FOLFIRI achieved 4 % RR and 2.5 months median PFS , versus FOLFOX6 which achieved 15 % RR and 4.2 months PFS . In first-line therapy , National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis , nausea/vomiting , and grade 2 alopecia were more frequent with FOLFIRI , and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6 . CONCLUSION Both sequences achieved a prolonged survival and similar efficacy . The toxicity profiles were different IMPORTANCE Future funding for new treatments in venous thromboembolism will be guided by cost-utility analyses . There is little available information on the utility of acute venous thromboembolism , limiting the validity of economic analyses . OBJECTIVE To measure the quality of life in the health states relating to thromboembolism cost-utility analyses . DESIGN A prospect i ve cohort study . SETTING A single-center , university-affiliated thrombosis clinic . PARTICIPANTS Two hundred sixteen thrombosis clinic patients with a history of lower limb deep vein thrombosis ( DVT ) or pulmonary embolism ( PE ) . EXPOSURES Participants consented to take a st and ard gamble interview . Each participant rated the quality of life in acute DVT , acute PE , and bleeding complication health states . MAIN OUTCOMES AND MEASURES The st and ard gamble measured quality of life ( utility value ) for acute DVT , acute PE , major intracranial bleeding event , minor intracranial bleeding event , and gastrointestinal bleeding event . RESULTS Two hundred fifteen responses were included in the analysis . Twenty-six percent had experienced both PE and DVT ; 54 % , DVT alone ; and 20 % , PE alone . Forty-two percent had experienced more than 1 episode of thrombosis , and 23 % had had cancer-associated thrombosis . We found the median utility for acute DVT was 0.81 ( interquartile range [ IQR ] , 0.55 - 0.94 ) ; acute PE , 0.75 ( IQR , 0.45 - 0.91 ) ; major intracranial bleeding event , 0.15 ( IQR , 0.00 - 0.65 ) ; minor intracranial bleeding event , 0.75 ( IQR , 0.55 - 0.92 ) ; and gastrointestinal bleeding event , 0.65 ( IQR , 0.15 - 0.86 ) . The median length of symptoms for DVT or PE was 1 week ( IQR , < 1 - 3 weeks ) . CONCLUSIONS AND RELEVANCE To our knowledge , this is the largest published study on utilities in which the participants had personal experience of venous thromboembolism . We present unique information for economic analyses but have also identified future challenges for research in this area . Our summary results differ from those previously published , and we found wide variation in individual responses BACKGROUND In the non-curative setting , the sequence in which anticancer agents are used , singly or in combination , may be important if patients are to receive the maximum period of disease control with the minimum of adverse effects . We compared sequential and combination chemotherapy strategies in patients with unpretreated advanced or metastatic colorectal cancer , who were regarded as not potentially curable irrespective of response . METHODS We studied patients with advanced colorectal cancer , starting treatment with non-curative intent . 2135 unpretreated patients were r and omly assigned to three treatment strategies in the ratio 1:1:1 . Strategy A ( control group ) was single-agent fluorouracil ( given with levofolinate over 48 h every 2 weeks ) until failure , then single-agent irinotecan . Strategy B was fluorouracil until failure , then combination chemotherapy . Strategy C was combination chemotherapy from the outset . Within strategies B and C , patients were r and omly assigned to receive , as the combination regimen , fluorouracil plus irinotecan ( groups B-ir and C-ir ) or fluorouracil plus oxaliplatin ( groups B-ox and C-ox ) . The primary endpoint was overall survival , analysed by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N 79877428 . RESULTS Median survival of patients allocated to control strategy A was 13.9 months . Median survival of each of the other groups was longer ( B-ir 15.0 , B-ox 15.2 , C-ir 16.7 , and C-ox 15.4 months ) . However , log-rank comparison of each group against control showed that only C-ir -- the first-line combination strategy including irinotecan -- satisfied the statistical test for superiority ( p=0.01 ) . Overall comparison of strategy B with strategy C was within the predetermined non-inferiority boundary of HR=1.18 or less ( HR=1.06 , 90 % CI 0.97 - 1.17 ) . INTERPRETATION Our data challenge the assumption that , in this non-curative setting , maximum tolerable treatment must necessarily be used first-line . The staged approach of initial single-agent treatment up grade d to combination when required is not worse than first-line combination , and is an alternative option for discussion with patients Background The results of R and omized Controlled Trials ( RCTs ) on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio . These do not constitute the sufficient statistics required for meta- analysis or cost-effectiveness analysis , and their use in secondary analyses requires strong assumptions that may not have been adequately tested . In order to enhance the quality of secondary data analyses , we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated . Methods We develop an algorithm that maps from digitised curves back to KM data by finding numerical solutions to the inverted KM equations , using where available information on number of events and numbers at risk . The reproducibility and accuracy of survival probabilities , median survival times and hazard ratios based on reconstructed KM data was assessed by comparing published statistics ( survival probabilities , medians and hazard ratios ) with statistics based on repeated reconstructions by multiple observers . Results The validation exercise established there was no material systematic error and that there was a high degree of reproducibility for all statistics . Accuracy was excellent for survival probabilities and medians , for hazard ratios reasonable accuracy can only be obtained if at least numbers at risk or total number of events are reported . Conclusion The algorithm is a reliable tool for meta- analysis and cost-effectiveness analyses of RCTs reporting time-to-event data . It is recommended that all RCTs should report information on numbers at risk and total number of events alongside KM curves BACKGROUND Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor ( EGFR ) therapy . Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy . METHODS In this prospect ive-retrospective analysis , we assessed the efficacy and safety of panitumumab plus oxaliplatin , fluorouracil , and leucovorin ( FOLFOX4 ) as compared with FOLFOX4 alone , according to RAS ( KRAS or NRAS ) or BRAF mutation status . A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following : KRAS exon 3 or 4 ; NRAS exon 2 , 3 , or 4 ; or BRAF exon 15 . The overall rate of ascertainment of RAS status was 90 % . RESULTS Among 512 patients without RAS mutations , progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone ( hazard ratio for progression or death with combination therapy , 0.72 ; 95 % confidence interval [ CI ] , 0.58 to 0.90 ; P=0.004 ) . Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group ( hazard ratio for death , 0.78 ; 95 % CI , 0.62 to 0.99 ; P=0.04 ) . A total of 108 patients ( 17 % ) with nonmutated KRAS exon 2 had other RAS mutations . These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment , which was consistent with the findings in patients with KRAS mutations in exon 2 .  BRAF mutations were a negative prognostic factor . No new safety signals were identified . CONCLUSIONS Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4 . In patients who had metastatic colorectal cancer without RAS mutations , improvements in overall survival were observed with panitumumab-FOLFOX4 therapy . ( Funded by Amgen and others ; PRIME Clinical Trials.gov number , NCT00364013 . ) BACKGROUND To determine the efficacy and tolerability of capecitabine combined with oxaliplatin ( CAPOX ) or irinotecan ( CAPIRI ) as first-line treatment in patients with advanced/metastatic colorectal cancer aged > or = 70 years . PATIENTS AND METHODS Patients aged > or = 70 years were r and omly assigned to receive CAPOX [ oxaliplatin 65 mg/m(2 ) intravenously ( i.v . ) days 1 and 8 and capecitabine 1000 mg/m(2 ) orally b.i.d . days 1 - 14 ; q21d ] or CAPIRI ( irinotecan 80 mg/m(2 ) i.v . days 1 and 8 and capecitabine 1000 mg/m(2 ) orally b.i.d . days 1 - 14 ; q21d ) . The primary study end point was overall response rate ( ORR ) . RESULTS Ninety-four patients were enrolled . In an intent-to-treat analysis , 2 complete responses ( CRs ) and 16 partial responses ( PRs ) were reported with CAPOX ( ORR 38 % ) , and 2 CRs and 15 PRs with CAPIRI ( ORR 36 % ; P = 0.831 ) . Median time to progression was 8 months for CAPOX and 7 months for CAPIRI ( P = 0.195 ) , with median survival times of 19.3 months and 14.0 months ( P = 0.165 ) , respectively . Global health status was improved in 45 % and in 21 % of patients in the CAPOX and CAPIRI arms , respectively . The most common treatment-related grade 3 - 4 adverse events in CAPIRI versus CAPOX patients were diarrhea ( 32 % versus 15 % ; P = 0.052 ) and neutropenia ( 23 % versus 6 % ; P = 0.021 ) . CONCLUSION CAPOX and CAPIRI had similar efficacy in elderly patients , although CAPOX seemed to be better tolerated BACKGROUND The OPUS study demonstrated that addition of cetuximab to 5-fluorouracil , folinic acid 
    Output:
    
First-line treatment with anti-EGFR therapies in combination with chemotherapy appeared to have statistically significant benefits for patients who are RAS WT .
No evidence was available for panitumumab plus FOLFIRI .
Although cetuximab and panitumumab in combination with chemotherapy appear to be clinical ly beneficial for RAS WT patients compared with chemotherapy alone , they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK .