***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: BACKGROUND Oxaliplatin combined with 5-fluorouracil ( 5-FU ) , with or without leucovorin ( LV ) , is effective and well tolerated for first-line therapy of advanced colorectal cancer ( CRC ) . However , there is no consensus as to which oxaliplatin/5-FU-containing regimen is superior in the first-line setting . This r and omized , multicenter phase II trial was design ed to evaluate and compare the efficacy of 4 different oxaliplatin/5-FU regimens . PATIENTS AND METHODS Patients with previously untreated metastatic CRC ( mCRC ; n = 129 ) were r and omized to 1 of 4 treatment regimens : ( 1 ) continuous 5-FU infusion plus oxaliplatin ( n = 23 ) ; ( 2 ) weekly 5-FU bolus with LV plus oxaliplatin ( n = 40 ) ; ( 3 ) oxaliplatin with 2-day infusion 5-FU/LV ( FOLFOX4 , n = 41 ) ; and ( 4 ) chronomodulated 5-FU plus oxaliplatin ( n = 25 ) . RESULTS Overall response rates , after expert assessment , ranged from 24 % to 34 % , and median progression-free survival ( PFS ) ranged from 6 months to 8 months . Although no significant differences in efficacy were detected in pairwise comparisons of the 4 different regimens , patients r and omized to FOLFOX4 had the highest response rate and longest PFS . The FOLFOX4 regimen was also associated with the lowest incidence of severe ( grade 3/4 ) toxicity , with the exception of cumulative peripheral neurotoxicity . CONCLUSION This r and omized phase II trial provides evidence that oxaliplatin/5-FU regimens are effective and well tolerated for first-line therapy of previously untreated mCRC . The FOLFOX regimens are now an established st and ard for CRC Pre clinical and clinical studies have demonstrated that the circadian modulation of 5-FU delivery may reduce toxicities and improve antitumor activity . However , the relative importance of the timing of 5-FU delivery has not been clinical ly addressed . The aims of this study were to determine the toxicities , the maximum tolerable doses and the activity of a regimen with 5-fluorouracil ( 5-FU ) and leucovorin ( LV ) administered as a 14-day continuous infusion according to a flat or three different chronomodulated rhythms in patients with metastatic gastrointestinal carcinomas . A total of 113 patients entered the study and their characteristics were comparable among the four groups . Toxicities included mainly stomatitis and diarrhea , and a reduced toxicity was observed in all the three chronogroups that allowed the delivery of higher dose intensities . Response rates were not significantly different among the four groups . These results suggest that a reduction in 5-FU+LV toxicity and an increase in 5-FU dose intensity can be obtained by a nonsinusoidally circadian modulated infusion . However , the reduction in toxicity observed seems to be dependent mainly on the quasi-intermittency and not on the timing of 5-FU+LV delivery BACKGROUND Chronotherapy is one of the several approaches to increase efficacy and reduce toxicity of chemotherapy . In a phase II study in the second-line in patients with metastatic colorectal cancer ( mCRC ) , we found that chronomodulated XELOX ( XELOX(30Chron ) ) was a well-tolerated regimen with potentially reduced toxicity . PATIENTS AND METHODS One hundred and forty-one patients with unresectable mCRC were enrolled in a r and omized study comparing st and ard XELOX ( XELOX(30 ) ) , arm A , and XELOX(30Chron ) , arm B-both with short-time infusion of oxaliplatin-with the primary aim of reducing overall toxicity . RESULTS Overall toxicity grade 2 - 4 was 90 % versus 85 % , P = 0.47 and grade 3 - 4 was 31 % versus 37 % , P = 0.6 in arm A and B , respectively . We found no significant differences in median overall survival ( 17.6 versus 15.5 months ; P = 0.068 ) and median progression-free survival ( 8.9 versus 8.8 months ; P = 0.7 ) . The incidence of grade 3 neuropathy was 16 % in arm A and 19 % in arm B ( P = 0.7 ) after a cumulative dose of oxaliplatin of 1000 mg/m(2 ) . CONCLUSION XELOX(30Chron ) does not reduce toxicity or improve efficacy . A 30-min infusion of oxaliplatin is safe and does not increase the severity of chronic neuropathy Animal studies have indicated that the time of administration of adriamycin and cisplatin , two widely used anticancer drugs , has a profound effect on their toxicity . This effect in cancer chemotherapy was studied in 31 patients with advanced ovarian cancer . Patients received at least eight monthly courses of adriamycin that were followed 12 hours later by cisplatin , with adriamycin r and omly administered at either 6 a.m. or 6 p.m. The results show that in the group receiving adriamycin in the evening and cisplatin in the morning ( i ) twice as many patients required reductions in dosage and delays in treatment , ( ii ) four times as many treatments had to be delayed , ( iii ) drug dosages had to be modified downward three times as often , and ( iv ) even with more dose attenuation and treatment delays , treatment complications were still about two times more common as in the group receiving adriamycin in the morning and cisplatin in the evening . These findings show that the circadian stage at which anticancer drugs are given to patients should be carefully considered The combination of protracted venous infusion ( PVI ) fluorouracil ( 5-FU ) and mitomycin-C has previously been shown to be superior to PVI 5-FU alone in terms of response rate and failure-free survival . This study explores the effect of dose intensification by circadian timing of 5-FU in this combination on response , toxicity , and survival .  Patients with advanced colorectal carcinoma were r and omized to receive PVI 5-FU 300 mg/m2 daily or circadian-timed infusion ( CTI ) of 5-FU , beginning at 600 mg/m2 and subsequently reduced to 450 mg/m2 , delivered as a flat-rate infusion from 10:15 PM to 9:45 AM . Both groups received mitomycin-C at a dose of 7 mg/m2 given every 6 weeks . From April 1996 to August 1998 , 320 patients were r and omized , including 263 with metastatic disease and 21 with circumferential margin involvement . The overall response rate for the PVI 5-FU group was 38 % , compared with 30.3 % for the CTI group ( P = 0.176 ) . There was no statistically significant difference in terms of failure-free survival ( 8.0 months vs. 9.9 months ; P = 0.131 ) or overall survival ( 15.8 months vs. 16.3 months ; P = 0.275 ) between the treatment groups . There were no differences in global quality of life . Grade 3/4 diarrhea occurred significantly more frequently with CTI 5-FU ( 6.5 % vs. 19.8 % ; P < 0.001 ) ; a nonsignificant trend toward increased incidences of grade 3/4 infection and palmar plantar erythema were observed with CTI 5-FU . This study confirms the high response rate and overall survival figures for the combination of PVI 5-FU and mitomycin-C in colorectal cancer . However , dose intensification of 5-FU using a circadian-timed , flat-rate infusion did not lead to improved response or survival 
    Output:
    
CONCLUSION Chronomodulated chemotherapy may be favorable to reduce the risks of certain side effects , but there is no current evidence for improvement in OS or ORR .
Our analysis suggests that the available data does not support the use of chronomodulated chemotherapy