***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 PURPOSE The aim of this r and omised trial was to evaluate the activity and toxicity of a biweekly regimen including 6S-leucovorin-modulated 5-fluorouracil ( LFA-5-FU ) , combined with either irinotecan ( CPT-11 + LFA 5-FU ) or raltitrexed ( Tomudex ) ( TOM + LFA-5-FU ) , in advanced colorectal cancer patients , and to make a preliminary comparison of both these experimental regimens with a biweekly administration of LFA-5-FU modulated by methotrexate ( MTX + LFA-5-FU ) . PATIENTS AND METHODS One hundred fifty-nine patients with advanced colorectal carcinoma previously untreated for the metastatic disease ( 34 of them previously exposed to adjuvant 5-FU ) were r and omly allocated to receive : CPT-11 , 200 mg/m2 i.v . on day 1 , followed on day 2 by LFA , 250 mg/m2 i.v . infusion and 5-FU , 850 mg/m2 s i.v . bolus ( arm A ) ; TOM , 3 mg/m2 i.v . on day 1 , followed on day 2 by LFA , 250 mg/m2 i.v . infusion and 5-FU , 1050 mg/m2 i.v . bolus ( arm B ) ; or MTX , 750 mg/m2 i.v . on day 1 , followed on day 2 by LFA , 250 mg/m2 i.v . infusion and 5-FU , 800 mg/m2 i.v . bolus ( arm C ) . Courses were repeated every two weeks in all arms of the trial . Response rate ( RR ) was evaluated after every four courses . The sample size was defined to have an 80 % power to detect a 35 % RR for each experimental treatment , and to show a difference of at least 4 % in RR with the st and ard treatment if the true difference is 15 % or more . RESULTS The RRs were : 34 % ( 95 % confidence interval ( 95 % , CI ) : 21%-48 % ) in arm A , including 3 complete responses ( CRs ) and 15 partial responses ( PRs ) , 24 % ( 95 % CI : 14%-38 % ) in arm B , including 2 CRs and 11 PRs , and 24 % ( 95 % CI : 14%-38 % ) , with 2 CRs and 11 PRs , in arm C. After a median follow-up time of 62 ( range 18 - 108 ) weeks , the median time to progression was 38 , 25 , and 27 weeks for arm A , B , and C , respectively . With 94 patients still alive , the one-year probability of survival was 61 % , 54 % , and 59 % , respectively . WHO grade 3 or 4 neutropenia and diarrhoea affected 46 % and 16 % , respectively , of patients treated with CPT-11 + LFA 5-FU .  Median relative dose intensity over eight cycles ( DI8 ) was 78 % for CPT-11 and 82 % for 5-FU .  Severe toxicities of TOM + LFA-5-FU were neutropenia ( 16 % ) and diarrhoea ( 16 % ) , but median relative DI8 was 93 % for TOM , and 82 % for 5-FU . CONCLUSIONS CPT-11 + LFA-5-FU compares favorably in term of activity and toxicity with other combination regimens including CPT-11 and continuous infusional 5-FU . The hypothesis of a RR 15 % higher than the MTX + LFA-5-FU treatment can not be ruled out after this interim analysis . The TOM + LFA 5-FU regimen showed a RR and a toxicity profile very close to the MTX + LFA 5-FU combination , and dose not deserve further evaluation in advanced colorectal cancer patients Elderly patients are recommended to have a reduced starting dose ( 300 mg m−2 once every 3 weeks ) of irinotecan monotherapy . The aims of this analysis are to compare toxicity and survival according to age , performance status ( PS ) , gender and prior radical pelvic radiotherapy ( RT ) . The primary end points were overall survival and an irinotecan-specific toxicity composite end point ( TCE ) defined as the occurrence of grade 3 or 4 diarrhoea , neutropenia , febrile neutropenia , fever , infection or nausea and vomiting .  Between 1997 and 2003 , 339 eligible patients with advanced colorectal cancer ( CRC ) progressing on or within 24 weeks of completing fluoropyrimidine-based chemotherapy were prospect ively registered in a multicentre r and omised trial . All patients commenced irinotecan at 350 mg m−2 once every 3 weeks . There were no differences in proportions of patients developing TCE by age ( < 70 vs ⩾70 : 37.8 vs 45.8 % ; P=0.218 ) , PS ( 0–1 vs 2 : 39.3 vs 41.5 % ; P=0.793 ) or prior RT ( RT vs no RT : 45.1 vs 38.5 % ; P=0.377 ) . Males experienced more toxicity than females ( 44.3 vs 32.6 % ; P=0.031 ) , but this was not significant after controlling for other co-variates ( P=0.06 ) . Patients aged ⩾70 had similar objective responses ( 11.1 vs 9 % ; P=0.585 ) and survival ( median 9.4 vs 9 months ; log rank P=0.74 ) compared to younger patients . Elderly patients derive the same benefit without experiencing more toxicity  with second-line irinotecan treatment for advanced CRC . Our data do not support the recommendation to reduce the starting dose for the elderly patients 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 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 
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targeted agents improved the efficacy of conventional chemotherapy both when considered together ( HR for OS : 0.84 , 95 % CI 0.77 to 0.91 ; 6 RCTs ; high- quality evidence ) and when bevacizumab was used alone ( HR for PFS : 0.67 , 95 % CI 0.60 to 0.75 ; 4 RCTs ; high- quality evidence ) .With regard to secondary endpoints , tumour response rates generally paralleled the survival results ; moreover , higher anticancer efficacy was generally associated with worse treatment-related toxicity , with the important exception of bevacizumab-containing regimens , where the addition of the targeted agent to chemotherapy did not result in a significant increase in the rate of SAE .
Finally , we found that oral ( instead of intravenous ) fluoropyrimidines significantly reduced the incidence of adverse effects ( without compromising efficacy ) in people treated with oxaliplatin-based regimens .
Systemic therapy offers a survival benefit to people with metastatic CRC who did not respond to first-line treatment , especially when targeted agents are combined with conventional chemotherapeutic drugs .