***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 The aim of this prospect i ve study was to assess the efficacy , clinical benefit and safety of CPT-11 ( irinotecan ) in patients with stringently-defined 5-fluorouracil-resistant metastatic colorectal cancer ( CRC ) . 107 patients with documented progression of metastatic CRC during 5-FU were treated with CPT-11 350 mg/m2 once every 3 weeks in a multicentre phase II study . Tumour response and toxicity were assessed using WHO criteria . Changes in performance status ( PS ) , weight and pain were also measured . The WHO response rate was 13/95 ( 13.7 % , 95 % CI 7.5 % to 22.3 % ) eligible patients with a median duration of response of 8.5 months ( 37 weeks , range : 18 - 53 + ) . There was also a high rate of disease stabilisation ( 44.2 % ) with a median duration of 4.8 months . The probability of being free of progression at 4 months was 50 % . Median survival from first administration of CPT-11 was 10.4 months or 45 weeks ( range : 3 - 66 + weeks ) . There was weight stabilisation or gain in 81 % ( 73/90 ) of patients , a favourable outcome in PS in 91 % ( 82/90 ) ( improvement of WHO PS 2 or stabilisation of PS 0 - 1 ) , and pain relief in 54 % ( 26/48 ) . There were no toxic deaths . Neutropenia was short-lasting and non-cumulative . Diarrhoea grade > or = 3 occurred in 7 % of cycles and 28/107 ( 26 % ) of patients . CPT-11 350 mg/m2 once every 3 weeks has an encouraging degree of activity in progressive metastatic CRC truly resistant to 5-FU with a relatively high rate of tumour growth control translated into clinical benefit . The toxicity profile of CPT-11 is becoming better understood and has been considerably improved 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 PURPOSE Irinotecan given until disease progression is an accepted st and ard treatment for advanced colorectal cancer ( CRC ) resistant to fluoropyrimidines . It is not known whether a predefined period of irinotecan treatment would result in similar duration of disease control . We performed a multicenter phase III trial to compare the two policies of defined- duration versus continuous irinotecan treatment . PATIENTS AND METHODS Three hundred thirty-three eligible patients with advanced CRC progressing on or within 24 weeks of completing fluoropyrimidine-based chemotherapy were prospect ively registered . After receiving eight cycles of irinotecan given at 350 mg/m2 once every 3 weeks , 55 patients with responding or stable disease were r and omly assigned to stop irinotecan ( n = 30 ) or continue until disease progression ( n = 25 ) . Registered patients were not r and omly assigned predominantly due to disease progression ( n = 236 ) and intolerable toxicity ( n = 38 ) . RESULTS From the time of r and om assignment , there were no differences in failure-free survival ( P = .999 ) or overall survival ( P = .11 ) between the two arms . No difference was seen in mean global health status quality -of-life score between the two arms at 12 weeks after r and om assignment . No grade 3 diarrhea and febrile neutropenia was seen in the continue-irinotecan arm after r and om assignment . CONCLUSION For most patients , the decision to continue on irinotecan beyond 24 weeks is influenced by disease progression or treatment-related toxicity . However , for 17 % of patients in whom this decision is clinical ly relevant , there seems to be little benefit from continuing irinotecan , though the drug was well tolerated without any deterioration in quality of life BACKGROUND Selective inhibition of cyclooxygenase-2 ( COX-2 ) may be associated with an increased risk of thrombotic events , but only limited long-term data have been available for analysis . We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor rofecoxib in a long-term , multicenter , r and omized , placebo-controlled , double-blind trial design ed to determine the effect of three years of treatment with rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas . METHODS A total of 2586 patients with a history of colorectal adenomas underwent r and omization : 1287 were assigned to receive 25 mg of rofecoxib daily , and 1299 to receive placebo . All investigator-reported serious adverse events that represented potential thrombotic cardiovascular events were adjudicated in a blinded fashion by an external committee . RESULTS A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up ( 1.50 events per 100 patient-years ) , as compared with 26 patients in the placebo group during 3327 patient-years of follow-up ( 0.78 event per 100 patient-years ) ; the corresponding relative risk was 1.92 ( 95 percent confidence interval , 1.19 to 3.11 ; P=0.008 ) . The increased relative risk became apparent after 18 months of treatment ; during the first 18 months , the event rates were similar in the two groups . The results primarily reflect a greater number of myocardial infa rct ions and ischemic cerebrovascular events in the rofecoxib group . There was earlier separation ( at approximately five months ) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure , pulmonary edema , or cardiac failure ( hazard ratio for the comparison of the rofecoxib group with the placebo group , 4.61 ; 95 percent confidence interval , 1.50 to 18.83 ) . Overall and cardiovascular mortality was similar in the two groups . CONCLUSIONS Among patients with a history of colorectal adenomas , the use of rofecoxib was associated with an increased cardiovascular risk PURPOSE In North America , no effective therapy has been available for patients with progressive metastatic colorectal cancer after front-line treatment with irinotecan , bolus fluorouracil ( FU ) , and leucovorin ( IFL ) .  PATIENTS AND METHODS Patients with metastatic colorectal cancer who progressed after IFL therapy  were r and omly assigned to bolus and infusional FU and leucovorin ( LV5FU2 ) , single-agent oxaliplatin , or the combination ( FOLFOX4 ) . This planned interim analysis evaluated objective response rate ( RR ) , time to tumor progression ( TTP ) , and alleviation of tumor-related symptoms ( TRS ) in an initial cohort of patients . RESULTS Between November 2000 and September 2001 , 463 patients from 120 sites in North America were r and omly assigned to treatment . FOLFOX4 proved superior to LV5FU2 in all measures of clinical efficacy . Objective RRs determined by an independent radiology panel were 9.9 % for FOLFOX4 versus 0 % for LV5FU2 ( Fisher 's exact test , P < .0001 ) . Median TTP was 4.6 months for FOLFOX4 versus 2.7 months for LV5FU2 ( two-sided , stratified log-rank test , P < .0001 ) . Relief of TRS occurred in 33 % of patients treated with FOLFOX4 versus 12 % of patients treated with LVFU2 ( chi2 test , P < .001 ) . Single-agent oxaliplatin was not superior to LV5FU2 in any measure of efficacy . Patients treated with FOLFOX4 experienced a higher incidence of clinical ly significant toxicities than patients treated with LV5FU2 , but these toxicities were predictable and did not result in a higher rate of treatment discontinuation or 60-day mortality rate . CONCLUSION For patients with metastatic colorectal cancer , second-line treatment with FOLFOX4 is superior to treatment with LVFU2 in terms of RR , TTP , and relief of TRS 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 
    Output:
    
Treatment groups did not differ significantly in overall QOL changes , response rate or progression free or overall-survival .
In a systematic review of 29 trials of second-line irinotecan-based treatment , single-agent irinotecan was associated with more diarrhoea and alopecia than the combination but efficacy was similar .
INTERPRETATION Combination treatment compared with single-agent irinotecan reduces alopecia and diarrhoea without compromising efficacy on clinical outcomes .