***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 The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis . So far , no phase 3 r and omised trials comparing the effectiveness of one targeted agent against another have been reported . We did a r and omised phase 3 study comparing axitinib , a potent and selective second-generation inhibitor of vascular endothelial growth factor ( VEGF ) receptors , with sorafenib , an approved VEGF receptor inhibitor , as second-line therapy in patients with metastatic renal cell cancer . METHODS We included patients coming from 175 sites ( hospitals and outpatient clinics ) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib , bevacizumab plus interferon-alfa , temsirolimus , or cytokines .  Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then r and omly assigned ( 1:1 ) to either axitinib ( 5 mg twice daily ) or sorafenib ( 400 mg twice daily ) . Axitinib dose increases to 7 mg and then to 10 mg , twice daily , were allowed for those patients without hypertension or adverse reactions above grade 2 . Participants were not masked to study treatment . The primary endpoint was progression-free survival ( PFS ) and was assessed by a masked , independent radiology review and analysed by intention to treat . This trial was registered on Clinical Trials.gov , number NCT00678392 . FINDINGS A total of 723 patients were enrolled and r and omly assigned to receive axitinib ( n=361 ) or sorafenib ( n=362 ) . The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib ( hazard ratio 0·665 ; 95 % CI 0·544 - 0·812 ; one-sided p<0·0001 ) . Treatment was discontinued because of toxic effects in 14 ( 4 % ) of 359 patients treated with axitinib and 29 ( 8 % ) of 355 patients treated with sorafenib . The most common adverse events were diarrhoea , hypertension , and fatigue in the axitinib arm , and diarrhoea , palmar-plantar erythrodysaesthesia , and alopecia in the sorafenib arm . INTERPRETATION Axitinib result ed in significantly longer PFS compared with sorafenib . Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma . FUNDING Pfizer Purpose Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma ( ARCC ) trial were conducted to assess the influence of tumor histology on outcome of patients treated with temsirolimus ( Torisel ™ ) or interferon-α ( IFN ) .  Patients and methods Patients with ARCC including clear cell and other types such as papillary and chromophobe histologies received either IFN ( 3 million units [ MU ] subcutaneously three times weekly , escalating to 18 MU ) or temsirolimus ( 25 mg intravenously weekly ) . Results Approximately 80 % of patients had clear cell and 20 % of patients had other histologies , the majority of which were papillary . Patients with clear cell and other RCC histologies , treated with temsirolimus , demonstrated comparable median overall and progression-free survival . In contrast , patients with other RCC histologies , treated with IFN , demonstrated shorter median overall and progression-free survival than patients with clear cell RCC . Hazard ratios for death for treatment with temsirolimus versus IFN were less than 1 for patients regardless of tumor histology . For patients treated with temsirolimus , 59 % with clear cell and 68 % with other RCC histologies experienced tumor reductions . For patients treated with IFN , 35 % with clear cell and 14 % with other RCC histologies had tumor reductions . However , temsirolimus did not appear to improve the objective response rate compared to IFN . Temsirolimus result ed in a superior clinical benefit rate compared with IFN , regardless of tumor histology . Conclusion Temsirolimus appears to be efficacious in patients with clear cell and non-clear cell histologies and can , therefore , be used for the treatment of all types of RCC BACKGROUND Combining targeted treatments for renal cell carcinoma has been suggested as a possible method to improve treatment efficacy . We aim ed to assess the potential synergistic or additive effect of the combination of bevacizumab , directed against the VEGF receptor , and temsirolimus , an mTOR inhibitor , in metastatic renal cell carcinoma . METHODS TORAVA was an open-label , multicentre r and omised phase 2 study undertaken in 24 centres in France . Patients aged 18 years or older who had untreated metastatic renal cell carcinoma were r and omly assigned ( 2:1:1 ) to receive the combination of bevacizumab ( 10 mg/kg every 2 weeks ) and temsirolimus ( 25 mg weekly ; group A ) , or one of the st and ard treatments : sunitinib ( 50 mg/day for 4 weeks followed by 2 weeks off ; group B ) , or the combination of interferon alfa ( 9 mIU three times per week ) and bevacizumab ( 10 mg/kg every 2 weeks ; group C ) . R and omisation was done central ly and independently from other study procedures with computer-generated permuted blocks of four and eight patients stratified by participating centre and Eastern Cooperative Oncology Group performance status . The primary endpoint was progression-free survival ( PFS ) at 48 weeks ( four follow-up CT scans ) , which was expected to be above 50 % in group A. Analysis was by intention to treat . The study is ongoing for long-term overall survival . This study is registered with Clinical Trials.gov , number NCT00619268 . FINDINGS Between March 3 , 2008 and May 6 , 2009 , 171 patients were r and omly assigned : 88 to the experimental group ( group A ) , 42 to group B , and 41 to group C.  PFS at 48 weeks was 29.5 % ( 26 of 88 patients , 95 % CI 20.0 - 39.1 ) in group A , 35.7 % ( 15 of 42 , 21.2 - 50.2 ) in group B , and 61.0 % ( 25 of 41 , 46.0 - 75.9 ) in group C. Median PFS was 8.2 months ( 95 % CI 7.0 - 9.6 ) in group A , 8.2 months ( 5.5 - 11.7 ) in group B , and 16.8 months ( 6.0 - 26.0 ) in group C. 45 ( 51 % ) of 88 patients in group A stopped treatment for reasons other than progression compared with five ( 12 % ) of 42 in group B and 15 ( 38 % ) of 40 in group C. Grade 3 or worse adverse events were reported in 68 ( 77 % ) of 88 patients in group A versus 25 ( 60 % ) of 42 in group B and 28 ( 70 % ) of 40 in group C. Serious adverse events were reported in 39 ( 44 % ) of 88 , 13 ( 31 % ) of 42 , and 18 ( 45 % ) of 40 patients in groups A , B , and C , respectively . INTERPRETATION The toxicity of the temsirolimus and bevacizumab combination was much higher than anticipated and limited treatment continuation over time . Clinical activity was low compared with the benefit expected from sequential use of each targeted therapy . This combination can not be recommended for first-line treatment in patients with metastatic renal cell carcinoma . FUNDING French Ministry of Health and Wyeth Pharmaceuticals PURPOSE Mature survival data and evaluation of vascular endothelial growth factor ( VEGF ) as a prognostic biomarker from the Treatment Approaches in Renal Cancer Global Evaluation Trial ( TARGET ) study in patients with renal cell carcinoma ( RCC ) are reported . PATIENTS AND METHODS Nine hundred three previously treated patients were r and omly assigned to receive sorafenib versus placebo . On demonstration of progression-free survival ( PFS ) benefit with sorafenib , patients assigned to placebo were offered sorafenib .  Overall survival ( OS ) was determined at two planned interim analyses and one final analysis , with a secondary OS analysis conducted by censoring placebo patients who crossed over to sorafenib . The relationships between baseline VEGF level and prognosis and efficacy were evaluated . RESULTS The final OS of patients receiving sorafenib was comparable with that of patients receiving placebo ( 17.8 v 15.2 months , respectively ; hazard ratio [ HR ] = 0.88 ; P = .146 ) ; however , when post-cross-over placebo survival data were censored , the difference became significant ( 17.8 v 14.3 months , respectively ; HR = 0.78 ; P = .029 ) . Adverse events at 16 months after cross over were similar to those previously reported . Baseline VEGF levels correlated with Eastern Cooperative Oncology Group performance status ( P < .0001 ) , Memorial Sloan-Kettering Cancer Center score ( P < .0001 ) , and PFS and OS in univariate ( PFS , P = .0013 ; OS , P = .0009 ) and multivariate ( PFS , P = .0231 ; OS , P = .0416 ) analyses of placebo patients and with short OS by multivariate analysis of patients receiving sorafenib ( P = .0145 ) . Both high-VEGF ( P < .01 ) and low-VEGF ( P < .01 ) groups benefited from sorafenib . CONCLUSION Although an OS benefit was not seen on a primary intent-to-treat analysis , results of a secondary OS analysis censoring placebo patients demonstrated a survival advantage for those receiving sorafenib , suggesting an important cross-over effect . VEGF levels are prognostic for PFS and OS in RCC . The results of TARGET establish the efficacy and safety of sorafenib in advanced RCC BACKGROUND We conducted a phase 3 , r and omized , double-blind , placebo-controlled trial of sorafenib , a multikinase inhibitor of tumor-cell proliferation and angiogenesis , in patients with advanced clear-cell renal-cell carcinoma . METHODS From November 2003 to March 2005 , we r and omly assigned 903 patients with renal-cell carcinoma that was resistant to st and ard therapy to receive either continuous treatment with oral sorafenib ( at a dose of 400 mg twice daily ) or placebo ;  451 patients received sorafenib and 452 received placebo .  The primary end point was overall survival . A single planned analysis of progression-free survival in January 2005 showed a statistically significant benefit of sorafenib over placebo . Consequently , crossover was permitted from placebo to sorafenib , beginning in May 2005 . RESULTS At the January 2005 cutoff , the median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group ( hazard ratio for disease progression in the sorafenib group , 0.44 ; 95 % confidence interval [ CI ] , 0.35 to 0.55 ; P<0.01 ) . The first interim analysis of overall survival in May 2005 showed that sorafenib reduced the risk of death , as compared with placebo ( hazard ratio , 0.72 ; 95 % CI , 0.54 to 0.94 ; P=0.02 ) , although this benefit was not statistically significant according to the O'Brien-Fleming threshold . Partial responses were reported as the best response in 10 % of patients receiving sorafenib and in 2 % of those receiving placebo ( P<0.001 ) . Diarrhea , rash , fatigue , and h and -foot skin reactions were the most common adverse events associated with sorafenib . Hypertension and cardiac ischemia were rare serious adverse events that were more common in patients receiving sorafenib than in those receiving placebo . CONCLUSIONS As compared with placebo , treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal-cell carcinoma in whom previous therapy has failed ; however , treatment is associated with increased toxic effects . ( Clinical Trials.gov number , NCT00073307 [ Clinical Trials.gov ] . ) BACKGROUND Everolimus ( RAD001 ) is an orally administered inhibitor of the mammalian target of rapamycin ( mTOR ) , a therapeutic target for metastatic renal cell carcinoma . We did a phase III , r and omised , double-blind , placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy . METHODS Patients with metastatic renal cell carcinoma which had progressed on sunitinib , sorafenib , or both , were r and omly assigned in a two to one ratio to receive everolimus 10 mg once daily ( n=272 )  or placebo  ( n=138 ) , in conjunction with best supportive 
    Output:
    
Overall , the data showed several targeted therapies were associated with an improvement in progression-free survival in patients with mRCC .
There were limited data from RCTs regarding the issue of sequencing ; studies on combination therapies have been hampered by difficulties with tolerability and safety .