***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: CONTEXT Medical evidence may be biased over time if completion and publication of r and omized efficacy trials are delayed when results are not statistically significant . OBJECTIVE To evaluate whether the time to completion and the time to publication of r and omized phase 2 and phase 3 trials are affected by the statistical significance of results and to describe the natural history of such trials . DESIGN Prospect i ve cohort of r and omized efficacy trials conducted by 2 trialist groups from 1986 to 1996 . SETTING Multicenter trial groups in human immunodeficiency virus infection sponsored by the National Institutes of Health . PATIENTS A total of 109 efficacy trials ( total enrollment , 43708 patients ) . MAIN OUTCOME MEASURES Time from start of enrollment to completion of follow-up and time from completion of follow-up to peer- review ed publication assessed with survival analysis . RESULTS The median time from start of enrollment to publication was 5.5 years and was substantially longer for negative trials than for results favoring an experimental arm ( 6.5 vs 4.3 years , respectively ; P<.001 ; hazard ratio for time to publication for positive vs negative trials , 3.7 ; 95 % confidence interval [ CI ] , 1.8 - 7.7 ) . This difference was mostly attributable to differences in the time from completion to publication ( median , 3.0 vs 1.7 years for negative vs positive trials ; P<.001 ) . On average , trials with significant results favoring any arm completed follow-up slightly earlier than trials with nonsignificant results ( median , 2.3 vs 2.5 years ; P=.045 ) , but long-protracted trials often had low event rates and failed to reach statistical significance , while trials that were terminated early had significant results . Positive trials were su bmi tted for publication significantly more rapidly after completion than were negative trials ( median , 1.0 vs 1.6 years ; P=.001 ) and were published more rapidly after su bmi ssion ( median , 0.8 vs 1.1 years ; P=.04 ) . CONCLUSION Among r and omized efficacy trials , there is a time lag in the publication of negative findings that occurs mostly after the completion of the trial follow-up PURPOSE The r and omized controlled trial ( RCT ) is the gold st and ard for establishing new therapies in clinical oncology . Here we document changes with time in design , sponsorship , and outcomes of oncology RCTs . METHODS Reports of RCTs evaluating  systemic therapy for breast , colorectal ( CRC ) , and non-small-cell lung cancer ( NSCLC ) published 1975 to 2004 in six major journals were review ed . Two authors abstract ed data regarding trial design , results , and conclusions . Conclusions of authors were grade d using a 7-point Likert scale . For each study the effect size for the primary end point was converted to a summary measure . RESULTS A total of 321 eligible RCTs were included ( 48 % breast , 24 % CRC , 28 % NSCLC ) . Over time , the number and size of RCTs increased considerably . For-profit/mixed sponsorship increased substantially during the study period ( 4 % to 57 % ; P < .001 ) . There was increasing use of time-to-event measures ( 39 % to 78 % ) and decreasing use of response rate ( 54 % to 14 % ) as primary end point ( P < .001 ) . Effect size remained stable over the study period . Authors have become more likely to strongly endorse the experimental arm ( P = .017 ) . A significant P value for the primary end point and industry sponsorship were each independently associated with endorsement of the experimental agent ( odds ratio [ OR ] = 19.6 , 95 % CI , 8.9 to 43.1 , and OR = 3.5 , 95 % CI , 1.6 to 7.5 , respectively ) . CONCLUSION RCTs in oncology have become larger and are more likely to be sponsored by industry . Authors of modern RCTs are more likely to strongly endorse novel therapies . For-profit sponsorship and statistically significant results are independently associated with endorsement of the experimental arm BACKGROUND Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib ( PLX4032 ) have shown response rates of more than 50 % in patients with metastatic melanoma with the BRAF V600E mutation . METHODS We conducted a phase 3 r and omized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated , metastatic melanoma with the BRAF V600E mutation . Patients were r and omly assigned to receive either vemurafenib ( 960 mg orally twice daily ) or dacarbazine ( 1000 mg per square meter of body-surface area intravenously every 3 weeks ) . Co primary end points were rates of overall and progression-free survival . Secondary end points included the response rate , response duration , and safety . A final analysis was planned after 196 deaths and an interim analysis after 98 deaths . RESULTS At 6 months , overall survival was 84 % ( 95 % confidence interval [ CI ] , 78 to 89 ) in the vemurafenib group and 64 % ( 95 % CI , 56 to 73 ) in the dacarbazine group . In the interim analysis for overall survival and final analysis for progression-free survival , vemurafenib was associated with a relative reduction of 63 % in the risk of death and of 74 % in the risk of either death or disease progression , as compared with dacarbazine ( P<0.001 for both comparisons ) . After review of the interim analysis by an independent data and safety monitoring board , crossover from dacarbazine to vemurafenib was recommended . Response rates were 48 % for vemurafenib and 5 % for dacarbazine . Common adverse events associated with vemurafenib were arthralgia , rash , fatigue , alopecia , keratoacanthoma or squamous-cell carcinoma , photosensitivity , nausea , and diarrhea ; 38 % of patients required dose modification because of toxic effects . CONCLUSIONS Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation . ( Funded by Hoffmann-La Roche ; BRIM-3 Clinical Trials.gov number , NCT01006980 . ) BACKGROUND The BOLERO-2 study previously demonstrated that adding everolimus ( EVE ) to exemestane ( EXE ) significantly improved progression-free survival ( PFS ) by more than twofold in patients with hormone-receptor-positive ( HR(+ ) ) , HER2-negative advanced breast cancer that recurred or progressed during/after treatment with nonsteroidal aromatase inhibitors ( NSAIs ) . The overall survival ( OS ) analysis is presented here . PATIENTS AND METHODS BOLERO-2 is a phase III , double-blind , r and omized international trial comparing EVE 10 mg/day plus EXE 25 mg/day versus placebo ( PBO ) + EXE 25 mg/day in postmenopausal women with HR(+ ) advanced breast cancer with prior exposure to NSAIs . The primary end point was PFS by local investigator assessment ; OS was a key secondary end point . RESULTS At the time of data cutoff ( 3 October 2013 ) , 410 deaths had occurred and 13 patients remained on treatment .  Median OS in patients receiving EVE + EXE was 31.0 months [ 95 % confidence interval ( CI ) 28.0 - 34.6 months ] compared with 26.6 months ( 95 % CI 22.6 - 33.1 months ) in patients receiving PBO + EXE ( hazard ratio = 0.89 ; 95 % CI 0.73 - 1.10 ; log-rank P = 0.14 ) . Post study treatments were received by 84 % of patients in the EVE + EXE arm versus 90 % of patients in the PBO + EXE arm . Types of post study therapies were balanced across arms , except for chemotherapy ( 53 % EVE + EXE versus 63 % PBO + EXE ) . No new safety concerns were identified . CONCLUSIONS In BOLERO-2 , adding EVE to EXE did not confer a statistically significant improvement in the secondary end point OS despite producing a clinical ly meaningful and statistically significant improvement in the primary end point , PFS ( 4.6-months prolongation in median PFS ; P < 0.0001 ) . Ongoing translational research should further refine the benefit of mTOR inhibition and related pathways in this treatment setting . TRIAL REGISTRATION NUMBER NCT00863655 BACKGROUND Sipuleucel-T , an autologous active cellular immunotherapy , has shown evidence of efficacy in reducing the risk of death among men with metastatic castration-resistant prostate cancer . METHODS In this double-blind , placebo-controlled , multicenter phase 3 trial , we r and omly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T ( 341 patients ) or placebo ( 171 patients ) administered intravenously every 2 weeks , for a total of three infusions . The primary end point was overall survival , analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen ( PSA ) and lactate dehydrogenase . RESULTS In the sipuleucel-T group , there was a relative reduction of 22 % in the risk of death as compared with the placebo group ( hazard ratio , 0.78 ; 95 % confidence interval [ CI ] , 0.61 to 0.98 ; P=0.03 ) . This reduction represented a 4.1-month improvement in median survival ( 25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group ) . The 36-month survival probability was 31.7 % in the sipuleucel-T group versus 23.0 % in the placebo group . The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test ( hazard ratio , 0.77 ; 95 % CI , 0.61 to 0.97 ; P=0.02 ) and after adjustment for use of docetaxel after the study therapy ( hazard ratio , 0.78 ; 95 % CI , 0.62 to 0.98 ; P=0.03 ) . The time to objective disease progression was similar in the two study groups . Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T.  Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills , fever , and headache . CONCLUSIONS The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer . No effect on the time to disease progression was observed . ( Funded by Dendreon ; Clinical Trials.gov number , NCT00065442 . Background : The correlation between efficacy end points in r and omized controlled trials ( RCTs ) of systemic therapy for non-Hodgkin 's lymphoma ( NHL ) was investigated to identify an appropriate surrogate end point for overall survival ( OS ) . Methods : RCTs of previously untreated NHL published from 1990 to 2009 were identified . Associations between absolute differences in efficacy end points were determined using nonparametric Spearman 's rank correlation coefficients ( rs ) . Results : Thirty-eight RCTs representing 85 treatment arms for aggressive NHL and 20 RCTs representing 42 arms for indolent NHL were included . For aggressive NHL , differences in 3-year progression-free survival (PFS)/event-free survival ( EFS ) were high correlated with differences in 5-year OS { rs of 0.90 [ 95 % confidence interval ( CI ) 0.73–0.96 ] } and linear regression determined that a 10 % improvement in 3-year EFS or PFS would predict for a 7 % ± 1 % improvement in 5-year OS . For indolent histology disease , differences in complete response were strongly correlated with differences in 3-year EFS [ rs 0.86 ( 95 % CI 0.35–0.97 ) ] , but there was no correlation between 3-year time-to-event end points and 5-year OS . Conclusions : Improvements in 3-year EFS/PFS are highly correlated with improvements in 5-year OS in aggressive NHL and should be explored as a c and i date surrogate end point . Definition of these relationships may inform future clinical trial design and interpretation of interim trial data This phase 1/2 study in patients with newly diagnosed multiple myeloma ( N = 53 ) assessed CRd -- carfilzomib ( 20 , 27 , or 36 mg/m2 , days 1 , 2 , 8 , 9 , 15 , 16 and 1 , 2 , 15 , 16 after cycle 8) , lenalidomide ( 25 mg/d , days 1 - 21 ) , and weekly dexamethasone ( 40/20 mg cycles 1 - 4/5+)--in 28-day cycles . After cycle 4 , transplantation-eligible c and i date s underwent stem 
    Output:
    
CONCLUSIONS AND RELEVANCE Most trial-level validation studies of surrogate end points in oncology find low correlations with survival .