***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 In the phase 3 KEYNOTE-024 trial , treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive , advanced non-small-cell lung cancer ( NSCLC ) with a programmed cell death-lig and 1 ( PD-L1 ) tumour proportion score of 50 % or greater ( PD-L1-positive ) . Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes ( PROs ) . METHODS In this multicentre , international , r and omised , open-label , phase 3 trial , we recruited patients with treatment-naive , stage IV NSCLC in 102 sites in 16 countries . Eligible patients had measurable disease ( per RECIST version 1.1 ) and an Eastern Cooperative Oncology Group ( ECOG ) performance status 0 or 1 . Patients were r and omly assigned ( 1:1 ) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks ( 35 cycles ) or investigator-choice platinum-doublet chemotherapy ( 4 - 6 cycles or until documented disease progression or unacceptable toxicity ) . R and omisation was stratified according to geography , ECOG performance status , and histology . PROs were assessed at day 1 of cycles 1 - 3 , every 9 weeks thereafter , at the treatment discontinuation visit , and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer ( EORTC ) Quality of Life Question naire Core 30 items ( QLQ-C30 ) , the EORTC Quality of Life Question naire Lung Cancer 13 items ( QLQ-LC13 ) , and the European Quality of Life 5 Dimensions-3 Level ( EQ-5D-3L ) question naire . The key exploratory PRO endpoints ( analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint ) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/ quality -of-life ( QOL ) score and time to deterioration of the composite of cough , chest pain , and dyspnoea in the QLQ-LC13 . This study is registered with Clinical Trials.gov , number NCT02142738 , and is ongoing but no longer enrolling patients . FINDINGS Between Sept 19 , 2014 , and Oct 29 , 2015 , 305 patients were r and omly assigned to pembrolizumab ( n=154 ) or chemotherapy ( n=151 ) . Three patients in each group did not complete any PRO instruments at any timepoints , and so 299 patients were included in the full analysis set . Of these patients , one in each group did not complete any PRO instruments before week 15 , and so were not included in analyses of change from baseline to week 15 . PRO compliance was greater than 90 % at baseline and approximately 80 % at week 15 for both groups . Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 ( 95 % CI 3·3 to 10·6 ) for pembrolizumab and -0·9 ( -4·8 to 3·0 ) for chemotherapy , for a difference of 7·8 ( 2·9 to 12·8 ; two-sided nominal p=0·0020 ) . Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients ( 46 [ 31 % ] of 151 patients vs 58 [ 39 % ] of 148 patients ) . Time to deterioration was longer with pembrolizumab than with chemotherapy ( median not reached [ 95 % CI 8·5 to not reached ] vs 5·0 months [ 3·6 to not reached ] ; hazard ratio 0·66 , 95 % CI 0·44 - 0·97 ; two-sided nominal p=0·029 ) . INTERPRETATION Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy , and might represent a new first-line st and ard of care for PD-L1-expressing , advanced NSCLC . FUNDING Merck & Composite outcomes , in which multiple end points are combined , are frequently used as primary outcome measures in r and omized trials and are often associated with increased statistical efficiency . However , such measures may prove challenging for the interpretation of results . In this article , we examine the use of composite outcomes in major clinical trials , assess the arguments for and against them , and provide guidance on their application and reporting . To assess incidence and quality of reporting , we systematic ally review ed the use of composite end points in clinical trials in Annals of Internal Medicine , BMJ , Circulation , Clinical Infectious Diseases , Journal of the American College of Cardiology , JAMA , Lancet , New Engl and Journal of Medicine , and Stroke from 1997 through 2001 using a sensitive search strategy . We selected for review 167 original reports of r and omized trials ( with a total of 300 276 patients ) that included a composite primary outcome that incorporated all-cause mortality .  Sixty-three trials ( 38 % ) were neutral both for the primary end point and the mortality component . Sixty trials ( 36 % ) reported significant results for the primary outcome measure but not for the mortality component . Only 6 trials ( 4 % ) were significant for the mortality component but not for the primary composite outcome , whereas 19 trials ( 11 % ) were significant for both . Twenty-two trials ( 13 % ) were inadequately reported . Our review suggests that reporting of composite outcomes is generally inadequate , implying that the results apply to the individual components of the composite outcome rather than only to the overall composite . Current guidelines for the undertaking and reporting of clinical trials could be revised to reflect the common use of composite outcomes in clinical trials BACKGROUND In the phase 3 RADIANT-4 trial , everolimus increased progression-free survival compared with placebo in patients with advanced , progressive , non-functional , well-differentiated gastrointestinal or lung neuroendocrine tumours ( NETs ) . We now report the health-related quality of life ( HRQOL ) secondary endpoint . METHODS RADIANT-4 is a multicentre , r and omised , double-blind , placebo-controlled , phase 3 trial done in 97 centres in 25 countries worldwide . Adults ( aged ≥18 years ) were eligible for the study if they had pathologically confirmed , advanced ( unresectable or metastatic ) , non-functional , well-differentiated ( grade 1 or 2 ) NETs of lung or gastrointestinal origin . Patients were r and omly allocated ( 2:1 ) using block r and omisation ( block size of three ) by an interactive voice response system to receive oral everolimus ( 10 mg per day ) or placebo , both with best supportive care , with stratification by tumour origin , WHO performance status , and previous somatostatin analogue treatment  . HRQOL was assessed with the Functional Assessment of Cancer Therapy-General ( FACT-G ) question naire at baseline ( visit 2 , day 1 ) , every 8 weeks ( ± 1 week ) during the study for the first 12 months after r and omisation , and every 12 weeks thereafter until study drug discontinuation . The primary endpoint , reported previously , was progression-free survival assessed by central review ; HRQOL was a prespecified secondary endpoint . The prespecified secondary outcome measure was time to definitive deterioration ( ≥7 points ) in FACT-G total score . Analyses were done on the full analysis set , consisting of all r and omised patients , by intention to treat . Only data obtained while receiving the r and omly allocated treatment were included in this analysis . Enrolment for RADIANT-4 was completed on Aug 23 , 2013 , but the trial is ongoing pending final analysis of the key secondary endpoint of overall survival . This trial is registered with Clinical Trials.gov , number NCT01524783 . FINDINGS Between April 3 , 2012 , and Aug 23 , 2013 , 302 patients were enrolled ; 205 were r and omly allocated everolimus and 97 were assigned placebo . At baseline , 193 ( 94 % ) of 205 patients assigned everolimus and 95 ( 98 % ) of 97 allocated placebo had completed either fully or partly the FACT-G question naire ; at week 48 , 70 ( 83 % ) of 84 patients assigned everolimus and 22 ( 85 % ) of 26 allocated placebo completed FACT-G. Median time to definitive deterioration in FACT-G total score was 11·27 months ( 95 % CI 9·27 - 19·35 ) with everolimus and 9·23 months ( 5·52-not estimable ) with placebo ( adjusted hazard ratio 0·81 , 95 % CI 0·55 - 1·21 ; log-rank p=0·31 ) . INTERPRETATION HRQOL was maintained for patients with advanced , non-functional , gastrointestinal or lung NETs , with no relevant differences noted between the everolimus and placebo groups . In view of the previous RADIANT-4 findings of longer progression-free survival  with everolimus , our findings suggest that everolimus delays disease progression while preserving overall HRQOL , even with the usual toxic effects related to active targeted drug treatment for cancer . FUNDING Novartis Pharmaceuticals Purpose In the phase III KEYNOTE-045 study ( Clinical Trials.gov identifier : NCT02256436 ) , pembrolizumab significantly prolonged overall survival compared with investigator 's choice of chemotherapy in patients with previously treated advanced urothelial cancer . Here , we report the results of health-related quality -of-life ( HRQoL ) analyses from the KEYNOTE-045 trial . Patients and Methods Patients were r and omly assigned 1:1 to pembrolizumab 200 mg or investigator 's choice of docetaxel 75 mg/m2 , paclitaxel 175 mg/m2 , or vinflunine 320 mg/m2 administered intravenously every 3 weeks . Key prespecified HRQoL analyses were time to deterioration ( TTD ) and mean change from baseline to week 15 in European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 global health status/ quality -of-life score . Results Of 542 patients who were r and omly assigned , 519 were included in HRQoL analyses ( pembrolizumab , n = 266 ; chemotherapy , n = 253 ) . HRQoL compliance was > 95 % at baseline and approximately 88 % at week 15 for both groups . Pembrolizumab prolonged TTD in global health status/ quality -of-life score compared with chemotherapy ( median , 3.5 months v 2.3 months ; hazard ratio , 0.72 ; nominal one-sided P = .004 ) . Mean ( 95 % CI ) change from baseline to week 15 in global health status/ quality -of-life score was 0.69 ( -2.40 to 3.77 ) with pembrolizumab and -8.36 ( -11.84 to -4.89 ) with chemotherapy ( mean difference , 9.05 points ; 95 % CI , 4.61 to 13.50 ; nominal two-sided P < .001 ) . Conclusion Pembrolizumab prolonged TTD in HRQoL compared with chemotherapy . Patients who were treated with pembrolizumab had stable or improved global health status/ quality of life , whereas those who were treated with investigator 's choice of chemotherapy experienced declines in global health status/ quality of life . Combined with efficacy and safety outcomes , these data support pembrolizumab as st and ard of care for patients with platinum-refractory advanced urothelial cancer In the Intergroupe Francophone de Cancérologie Thoracique 0501 trial the carboplatin-paclitaxel chemotherapy increased toxicity ( most frequent , decreased neutrophil count , asthenia ) . We longitudinally compared health-related quality of life ( HRQoL ) of the two treatment arms . In total , 451 patients aged 70–89 years with advanced non-small cell lung cancer ( NSCLC ) were r and omly assigned to receive carboplatin plus paclitaxel or vinorelbine or gemcitabine .  HRQoL was assessed by means of the European Organisation for Research and Treatment of Cancer QLQ-C30 question naire at baseline , week 6 and week 18 . Using a five-point decrease as the minimal clinical ly important difference , patients treated with the chemotherapy doublet exhibited a significant longer time until definitive deterioration ( TUDD ) for two HRQoL dimensions : physical functioning ( median TUDD : 2.04 for the doublet versus 1.71 months for monotherapy ; log-rank p=0.01 ) and nausea and vomiting ( median : not reached versus 4.83 , respectively ; log-rank p=0.046 ) . Cox multivariate analysis revealed the carboplatin and 
    Output:
    
This review highlights the lack of st and ardization of the TTD approach for the analysis of PRO data in RCTs .