***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 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 This study evaluates the efficacy of capecitabine using data from a large , well-characterised population of patients with metastatic colorectal cancer ( mCRC ) treated in two identically design ed phase III studies . A total of 1207 patients with previously untreated mCRC were r and omised to either oral capecitabine ( 1250 mg m−2 twice daily , days 1−14 every 21 days ; n=603 ) or intravenous ( i.v . ) bolus 5-fluorouracil/leucovorin ( 5-FU/LV ; Mayo Clinic regimen ; n=604 ) . Capecitabine demonstrated a statistically significant superior response rate compared with 5-FU/LV ( 26 vs 17 % ; P<0.0002 ) . Subgroup analysis demonstrated that capecitabine consistently result ed in superior response rates ( P<0.05 ) , even in patient subgroups with poor prognostic indicators . The median time to response and duration of response were similar and time to progression ( TTP ) was equivalent in the two arms ( hazard ratio ( HR ) 0.997 , 95 % confidence interval ( CI ) 0.885–1.123 , P=0.95 ; median 4.6 vs 4.7 months with capecitabine and 5-FU/LV , respectively ) . Multivariate Cox regression analysis identified younger age , liver metastases , multiple metastases and poor Karnofsky Performance Status as independent prognostic indicators for poor TTP . Overall survival was equivalent in the two arms ( HR 0.95 , 95 % CI 0.84–1.06 , P=0.48 ; median 12.9 vs 12.8 months , respectively ) . Capecitabine results in superior response rate , equivalent TTP and overall survival , an improved safety profile and improved convenience compared with i.v . 5-FU/LV as first-line treatment for MCRC . For patients in whom fluoropyrimidine monotherapy is indicated , capecitabine should be strongly considered . Following encouraging results from phase I and II trials , r and omised trials are evaluating capecitabine in combination with irinotecan , oxaliplatin and radiotherapy . Capecitabine is a suitable replacement for i.v . 5-FU as the backbone of colorectal cancer therapy Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more PURPOSE To verify the experience of the GOIM in the treatment of advanced colorectal cancer patients with the FOLFIRI combination therapy .  PATIENTS AND METHODS Patients entered in three consecutive trials of the GOIM ( protocol s no. 9706 , 9901 , and 2301 ) were reported in this analysis . A total of 287 chemotherapy-naive patients were treated with FOLFIRI regimen : Irinotecan 180 mg/m(2 ) on day 1 with LV5FU2 regimen ( LV at 100 mg/m(2 ) administered as a 2-hour infusion before FU at 400 mg/m(2 ) as an intravenous bolus injection , and FU at 600 mg/m(2 ) as a 22-hour infusion immediately after 5FU bolus injection on day 1 and 2 ) ; the treatment was repeated every 2 weeks . RESULTS 287 patients entered in these three trials , and 264 ( 92 % ) were evaluable for response . The overall response rate was 34.5 % ( 95 % confidence interval [ CI ] : 29 % to 40 % ) . When only assessable patients were analyzed , overall response rate was 37 % ( 95 % CI : 31 % to 43 % ) . Median time to progression , median duration of response and survival were 7 months , 10.5 months and 14 months , respectively . All but three patients were evaluable for toxicity which was globally mild ; grade 3 - 4 toxicity was uncommon , and gastrointestinal disturbances were the most common . CONCLUSIONS FOLFIRI regimen is effective and well-tolerated as first-line treatment in patients with advanced colorectal cancer . Further studies needed to evaluate the improvement in results with the addition of new drugs to this combination therapy One hundred and ninety-three patients were assigned to receive 5-FU/LV , irinotecan and oxaliplatin in five different sequential treatment groups : Mayo Clinic Regimen ( MCR ) + LV5FU2 ( group A ) ; MCR + irinotecan ( 350 mg/m2 ) ( group B ) ; MCR + FOLFIRI ( group C ) ; MCR + FOLFOX4 ( group D ) ; FOLFIRI + FOLFOX4 ( group E ) . The results were as follows : group A ( 32 patients ) , median overall survival ( OS ) 14 months , median time to progression ( TTP1 ) 6 months , median TTP2 5 months , response rate ( RR1 ) 22 % , RR2 25 % ; group B ( 27 patients ) , OS 11 months , TTP1 6 months , TTP2 3 months , RR1 22 % , RR2 19 % ; group C ( 43 patients ) , OS 14 months , TTP1 5 months , TTP2 5 months , RR1 12 % , RR2 19 % ; group D ( 45 patients ) , OS 15 months , TTP1 5 months , TTP2 4 months , RR1 18 % , RR2 20 % ; group E ( 46 patients ) , OS 19 months , TTP1 9 months , TTP2 5 months , RR1 39 % , RR2 25 % . There was a significant difference in OS ( p < 0.005 ) between groups E vs. B and A , D vs. B. Sequential therapy with 3 active drugs ( FOLFIRI + FOLFOX4 ) was the most efficacious combination in comparison with any other two drug combinations applied in our study This multicenter , Phase II trial was performed to evaluate the antitumor activity and toxicity of irinotecan ( CPT‐11 ) in patients with metastatic colorectal carcinoma that had recurred or progressed after 5‐fluorouracil (5‐FU)‐based chemotherapy BACKGROUND Three different therapeutic regimens of irinotecan ( CPT-11 ) in combination with 5-fluorouracil ( 5-FU ) and folinic acid ( FA ) were evaluated for efficacy and safety in the first-line therapy of advanced colorectal cancer . PATIENTS AND METHODS Patients were r and omly assigned to receive intravenously either : CPT-11 125 mg/m(2 ) , FA 20 mg/m(2 ) followed by 5-FU 500 mg/m(2 ) bolus , weekly for 4 weeks ( arm A , Saltz regimen ) ; or CPT-11 180 mg/m(2 ) day 1 then FA 200 mg/m(2 ) over 2 h and 5-FU 400 mg/m(2 ) bolus and 5-FU 600 mg/m(2 ) 22-h infusion on days 1 and 2 , every 2 weeks ( arm B , Douillard regimen ) ; or CPT-11 350 mg/m(2 ) ( days 1 and 43 ) alternating with FA 20 mg/m(2)/day followed by 5-FU bolus 425 mg/m(2)/day during 5 days ( days 22 - 26 ) ( arm C , Mayo Clinic regimen ) . RESULTS A total of 154 patients were included in the study ( arm A , 51 patients ; arm B , 53 ; arm C , 50 ) . Overall response rates for the intention-to-treat population s were 33 % [ 95 % confidence interval ( CI ) 21 % to 48 % ] , 42 % ( 95 % CI 28 % to 56 % ) and 30 % ( 95 % CI 18 % to 45 % ) for arms A , B and C , respectively . Median times to progression were 6 , 8 and 7 months for arms A , B and C , respectively . Median survival times were 15 , 12 and 17 months for arms A , B and C , respectively . Overall response rates for the evaluable patient population s were 40 % ( 95 % CI 24 % to 58 % ) in arm A 
    Output:
    
There were higher risks of toxicity outcomes grade 3 or 4 diarrhoea and grade 1 or 2 alopecia , and a lower risk of grade 3 or 4 neutropenia in controls compared to the invervention group .
There was no overall survival benefit of the irinotecan and fluoropyrimidine treatment over irinotecan alone , thus both regimens remain reasonable options in treating patients with advanced or metastatic CRC .