***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: This is the last in a series of four articles Prognostic studies include clinical studies of variables predictive of future events as well as epidemiological studies of aetiological risk factors . As multiple similar studies accumulate it becomes increasingly important to identify and evaluate all of the relevant studies to develop a more reliable overall assessment . For prognostic studies this is not straightforward . Box 1 summarises the clinical importance of information on prognostic factors . Many of the issues discussed are also relevant to aetiological studies , especially cohort ones . Some features of prognostic studies lead to particular difficulties for the systematic review er . Firstly , in most clinical prognostic studies the outcome of primary interest is the time to an event , often death . Meta- analysis of such studies is rather more difficult than that for binary data or continuous measurements . Secondly , in many context s the prognostic variable of interest is often one of several prognostic variables . When examining a variable of interest research ers should consider other prognostic variables with which it might be correlated . Thirdly , many prognostic factors are continuous variables , for which research ers use a wide variety of methods of analysis . # # # # Summary points Systematic review s are applicable to all types of research design , and studies of prognostic variables are an important additional area where appropriate methodology should be applied Prognostic variables should be evaluated in a representative sample of patients assembled at a common point in the course of their disease — ideally they should all have received the same medical treatment or been in a r and omised trial When examined critically , a high proportion of prognostic studies are found to be method ologically poor Meta- analysis of published data is hampered by difficulties in extraction of data and variation in the characteristics of the study and patients The poor quality of the published literature is a strong argument in favour 5-Fluorouracil ( 5-FU ) remains the mainstay of treatment for advanced colorectal carcinoma , although response rates are generally less than 20 % . Improved therapeutic efficacy has been reported using biochemical modulation of 5-FU by leucovorin ( LV ) or interferon alpha ( IFN ) , the combination of 5-FU/LV frequently considered as st and ard therapy in metastatic colorectal cancer . In an attempt to enhance the cytotoxicity of 5-FU , a prospect i ve r and omised trial was initiated to compare 5-FU/LV with 5-FU/LV plus IFN .  Patients were r and omised to receive either LV , 100 mg/m2 intravenously ( i.v . ) , followed by 5-FU , 500 mg/m2 as a 1-h i.v . infusion , daily for 4 days , followed by weekly infusions until week 8 , or the same regimen of 5-FU/LV plus IFN-alpha-2c , 30 micrograms subcutaneously ( s.c . ) , three times weekly . Cycles were repeated after a 2-week rest period . Among 269 enrolled patients , 219 were available for response and 243 for toxicity . An objective tumour response was observed in 38 of 107 ( 36 % ) and 28 of 112 ( 25 % ) patients in the treatment arms with and without IFN , respectively ( difference not significant ) . There was no significant difference between the two groups in response duration ( median 8.4 versus 12.1 months ) , time to treatment failure ( median 6.5 versus 4.9 months ) , or overall survival ( median 10.0 versus 12.6 months ) . However , patients in the IFN arm experienced significantly more haematological and gastrointestinal toxicity and more frequent alopecia . In conclusion , the addition of IFN to 5-FU/LV in the schedules and doses used in the study did not provide any clinical benefit over 5-FU/LV alone and can not be recommended for routine use in the treatment of advanced colorectal cancer BACKGROUND The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined . Our aim was to investigate whether combination treatment is better than sequential administration of the same drugs in patients with advanced colorectal cancer . METHODS We r and omly assigned 820 patients with advanced colorectal cancer to receive either first-line treatment with capecitabine , second-line irinotecan , and third-line capecitabine plus oxaliplatin ( sequential treatment ; n=410 ) or first-line treatment capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin ( combination treatment ; n=410 ) . The primary endpoint was overall survival . Analyses were done by intention to treat . This trial is registered with Clinical Trials.gov with the number NCT00312000 . FINDINGS 17 patients ( nine in the sequential treatment group , eight in the combination group ) were found to be ineligible and were excluded from the analysis . 675 ( 84 % ) patients died during the study : 336 in the sequential group and 339 in the combination group . Median overall survival was 16.3 ( 95 % CI 14.3 - 18.1 ) months for sequential treatment and 17.4 ( 15.2 - 19.2 ) months for combination treatment ( p=0.3281 ) . The hazard ratio for combination versus sequential treatment was 0.92 ( 95 % CI 0.79 - 1.08 ; p=0.3281 ) . The frequency of grade 3 - 4 toxicity over all lines of treatment did not differ significantly between the two groups , except for grade 3 h and -foot syndrome , which occurred more often with sequential treatment than with combination treatment ( 13%vs 7 % ; p=0.004 ) . INTERPRETATION Combination treatment does not significantly improve overall survival compared with the sequential use of cytotoxic drugs in advanced colorectal cancer . Thus sequential treatment remains a valid option for patients with advanced colorectal cancer OBJECTIVE To assess the method ologic quality of approaches used to allocate participants to comparison groups in r and omized controlled trials from one medical specialty . DESIGN Survey of published , parallel group r and omized controlled trials . DATA SOURCES All 206 reports with allocation described as r and omized from the 1990 and 1991 volumes of four journals of obstetrics and gynecology . MAIN OUTCOME MEASURES Direct and indirect measures of the adequacy of r and omization and baseline comparisons . RESULTS Only 32 % of the reports described an adequate method for generating a sequence of r and om numbers , and only 23 % contained information showing that steps had been taken to conceal assignment until the point of treatment allocation . A mere 9 % described both sequence generation and allocation concealment . In reports of trials that had apparently used unrestricted r and omization , the differences in sample sizes between treatment and control groups were much smaller than would be expected due to chance . In reports of trials in which hypothesis tests had been used to compare baseline characteristics , only 2 % of reported test results were statistically significant , lower than the expected rate of 5 % . CONCLUSIONS Proper r and omization is required to generate unbiased comparison groups in controlled trials , yet the reports in these journals usually provided inadequate or unacceptable information on treatment allocation . Additional analyses suggest that nonr and om manipulation of comparison groups and selective reporting of baseline comparisons may have occurred PURPOSE In a previous study of treatment for advanced colorectal cancer , the LV5FU2 regimen , comprising leucovorin ( LV ) plus bolus and infusional fluorouracil ( 5FU ) every 2 weeks , was superior to the st and ard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen . This phase III study investigated the effect of combining oxaliplatin with LV5FU2 , with progression-free survival as the primary end point . PATIENTS AND METHODS Four hundred twenty previously untreated patients with measurable disease were r and omized to receive a 2-hour infusion of LV ( 200 mg/m(2)/d ) followed by a 5FU bolus ( 400 mg/m(2)/d ) and 22-hour infusion ( 600 mg/m(2)/d ) for 2 consecutive days every 2 weeks , either alone or together with oxaliplatin 85 mg/m(2 ) as a 2-hour infusion on day 1 . RESULTS Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival ( median , 9.0 v 6.2 months ; P = .0003 ) and better response rate ( 50.7 % v 22.3 % ; P = .0001 ) when compared with the control arm . The improvement in overall survival did not reach significance ( median , 16.2 v 14.7 months ; P = . 12 ) . LV5FU2 plus oxaliplatin gave higher frequencies of National Cancer Institute common toxicity criteria grade 3/4 neutropenia ( 41 . 7 % v 5.3 % of patients ) , grade 3/4 diarrhea ( 11.9 % v 5.3 % ) , and grade 3 neurosensory toxicity ( 18.2 % v 0 % ) , but this did not result in impairment of quality of life ( QoL ) . Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment ( P = .004 ) . CONCLUSION The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer , demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of 
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However , the effect on PFS shows significant heterogeneity .
While differences in treatment-related deaths and 60-day mortality were not significant , higher incidences in grade III/IV hypertension , arterial thrombembolic events and gastrointestinal perforations were observed in the patients treated with bevacizumab .
For valatanib , currently available data showed a non-significant benefit in PFS and OS .
AUTHORS ' CONCLUSIONS The addition of bevacizumab to chemotherapy of metastatic colorectal cancer prolongs both PFS and OS in first- and second-line therapy