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:
The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials
Abstract 1:
Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more


Title 2:
Vascular effects, efficacy and safety of nintedanib in patients with advanced, refractory colorectal cancer: a prospective phase I subanalysis
Abstract 2:
Background Nintedanib is a potent , oral angiokinase inhibitor that targets VEGF , PDGF and FGF signalling , as well as RET and Flt3 . The maximum tolerated dose of nintedanib was evaluated in a phase I study of treatment-refractory patients with advanced solid tumours . In this preplanned sub analysis , the effect of nintedanib on the tumour vasculature , along with efficacy and safety , was assessed in 30 patients with colorectal cancer ( CRC ) . Methods Patients with advanced CRC who had failed conventional treatment , or for whom no therapy of proven efficacy existed , were treated with nintedanib ranging from 50–450 mg once-daily ( n = 14 ) or 150–250 mg twice-daily ( n = 16 ) for 28 days . After a 1-week rest , further courses were permitted in the absence of progression or undue toxicity . The primary objective was the effect on the tumour vasculature using dynamic contrast-enhanced magnetic resonance imaging ( DCE-MRI ) and expressed as the initial area under the DCE-MRI contrast agent concentration – time curve after 60 seconds ( iAUC60 ) or the volume transfer constant between blood plasma and extravascular extracellular space ( Ktrans ) . Results Patients received a median of 4.0 courses ( range : 1–13 ) . Among 21 evaluable patients , 14 ( 67 % ) had a ≥40 % reduction from baseline in Ktrans and 13 ( 62 % ) had a ≥40 % decrease from baseline in iAUC60 , representing clinical ly relevant effects on tumour blood flow and permeability , respectively . A ≥40 % reduction from baseline in Ktrans was positively associated with non-progressive tumour status ( Fisher ’s exact : p = 0.0032 ) . One patient achieved a partial response at 250 mg twice-daily and 24 ( 80 % ) achieved stable disease lasting ≥8 weeks . Time to tumour progression ( TTP ) at 4 months was 26 % and median TTP was 72.5 days ( 95 % confidence interval : 65–114 ) . Common drug-related adverse events ( AEs ) included nausea ( 67 % ) , vomiting ( 53 % ) and diarrhoea ( 40 % ) ; three patients experienced drug-related AEs ≥ grade 3 . Four patients treated with nintedanib once-daily had an alanine aminotransferase and /or aspartate aminotransferase increase ≥ grade 3 . No increases > grade 2 were seen in the twice-daily group . Conclusions Nintedanib modulates tumour blood flow and permeability in patients with advanced , refractory CRC , while achieving antitumour activity and maintaining an acceptable safety profile


Title 3:
Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial.
Abstract 3:
BACKGROUND The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer ( NSCLC ) . METHODS Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy , stratified by ECOG performance status , previous bevacizumab treatment , histology , and presence of brain metastases , were allocated ( by computer-generated sequence through an interactive third-party system , in 1:1 ratio ) , to receive docetaxel 75 mg/m(2 ) by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2 - 21 , every 3 weeks until unacceptable adverse events or disease progression . Investigators and patients were masked to assignment . The primary endpoint was progression-free survival ( PFS ) by independent central review , analysed by intention to treat after 714 events in all patients . The key secondary endpoint was overall survival , analysed by intention to treat after 1121 events had occurred , in a prespecified stepwise order : first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy , then in all patients with adenocarcinoma , then in all patients . This trial is registered with Clinical Trials.gov , number NCT00805194 . FINDINGS Between Dec 23 , 2008 , and Feb 9 , 2011 , 655 patients were r and omly assigned to  receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo . The primary analysis was done after a median follow-up of 7·1 months ( IQR 3·8 - 11·0 ) . PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group ( median 3·4 months [ 95 % CI 2·9 - 3·9 ] vs 2·7 months [ 2·6 - 2·8 ] ; hazard ratio [ HR ] 0·79 [ 95 % CI 0·68 - 0·92 ] , p=0·0019 ) . After a median follow-up of 31·7 months ( IQR 27·8 - 36·1 ) , overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group ( 206 patients ) compared with those in the docetaxel plus placebo group ( 199 patients ; median 10·9 months [ 95 % CI 8·5 - 12·6 ] vs 7·9 months [ 6·7 - 9·1 ] ; HR 0·75 [ 95 % CI 0·60 - 0·92 ] , p=0·0073 ) . Similar results were noted for all patients with adenocarcinoma histology ( 322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group ; median overall survival 12·6 months [ 95 % CI 10·6 - 15·1 ] vs 10·3 months [ 95 % CI 8·6 - 12·2 ] ; HR 0·83 [ 95 % CI 0·70 - 0·99 ] , p=0·0359 ) , but not in the total study population ( median 10·1 months [ 95 % CI 8·8 - 11·2 ] vs 9·1 months [ 8·4 - 10·4 ] ; HR 0·94 , 95 % CI 0·83 - 1·05 , p=0·2720 ) . Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea ( 43 [ 6·6 % ] of 652 vs 17 [ 2·6 % ] of 655 ) , reversible increases in alanine aminotransferase ( 51 [ 7·8 % ] vs six [ 0·9 % ] ) , and reversible increases in aspartate aminotransferase ( 22 [ 3·4 % ] vs three [ 0·5 % ] ) . 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression ; the most common of these events were sepsis ( five with docetaxel plus nintedanib vs one with docetaxel plus  placebo ) , pneumonia ( two vs seven ) , respiratory failure ( four vs none ) , and pulmonary embolism ( none vs three ) . INTERPRETATION Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy , especially for patients with adenocarcinoma . FUNDING Boehringer Ingelheim
No heterogeneity was observed despite different drugs .
Protracted inhibition of the VEGF pathway is associated with a significant improvement of both PFS and OS , independently from the antiangiogenic agent used