You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.



Title 1:
A four-arm, randomized, multicenter phase II trial of oxaliplatin combined with varying schedules of 5-fluorouracil as first-line therapy in previously untreated advanced colorectal cancer.
Abstract 1:
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


Title 2:
Infusions of Fluorouracil and Leucovorin: Effects of the Timing and Semi-Intermittency of Drug Delivery
Abstract 2:
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


Title 3:
A randomized study comparing short-time infusion of oxaliplatin in combination with capecitabine XELOX(30) and chronomodulated XELOX(30) as first-line therapy in patients with advanced colorectal cancer.
Abstract 3:
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


Title 4:
Circadian timing of cancer chemotherapy.
Abstract 4:
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


Title 5:
Phase III study of mitomycin-C with protracted venous infusion or circadian-timed infusion of 5-fluorouracil in advanced colorectal carcinoma.
Abstract 5:
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
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