***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 perception that older cancer patients may be at higher risk than younger patients of toxic effects from cancer therapy but may obtain less clinical benefit from it may be based on the underrepresentation of older patients in clinical trials and the known toxic effects of cytotoxic chemotherapy . It is not known how older patients respond to targeted therapy . Methods This retrospective subgroup analysis of data from the phase 3 , r and omized Treatment Approach in Renal Cancer Global Evaluation Trial examined the safety and efficacy of sorafenib in older ( age ≥70 years , n = 115 ) and younger patients ( age < 70 years , n = 787 ) who received treatment for advanced renal cell carcinoma . Patient demographics and progression-free survival were recorded . Best tumor response , clinical benefit rate ( defined as complete response plus partial response plus stable disease ) , time to self-reported health status deterioration , and toxic effects were assessed by descriptive statistics . Health-related quality of life was assessed with a Cox proportional hazards model . Kaplan – Meier analyses were used to summarize time-to-event data . Results Median progression-free survival was similar in sorafenib-treated younger patients ( 23.9 weeks ; hazard ratio [ HR ] for progression compared with placebo = 0.55 , 95 % confidence interval [ CI ] = 0.47 to 0.66 ) and older patients ( 26.3 weeks ; HR = 0.43 , 95 % CI = 0.26 to 0.69 ) . Clinical benefit rates among younger and older sorafenib-treated patients were also similar ( 83.5 % and 84.3 % , respectively ) and were superior to those of younger and older placebo-treated patients ( 53.8 % and 62.2 % , respectively ) . Adverse events were predictable and manageable regardless of age . Sorafenib treatment delayed the time to self-reported health status deterioration among both older patients ( 121 days with sorafenib vs 85 days with placebo ; HR = 0.66 , 95 % CI = 0.43 to 1.03 ) and younger patients ( 90 days with sorafenib vs 52 days with placebo ; HR = 0.69 , 95 % CI = 0.59 to 0.81 ) and improved quality of life over that time . Conclusions Among patients with advanced renal cell carcinoma receiving sorafenib treatment , outcomes of older ( ≥70 years ) and younger ( < 70 years ) patients were similar PURPOSE The antitumor activity and safety of tivozanib , which is a potent and selective vascular endothelial growth factor receptor-1 , -2 , and -3 inhibitor , was assessed in patients with advanced/metastatic renal cell carcinoma ( RCC ) . PATIENTS AND METHODS In this phase II , r and omized discontinuation trial , 272 patients received open-label tivozanib 1.5 mg/d ( one cycle equaled three treatment weeks followed by a 1-week break ) orally for 16 weeks . Thereafter , 78 patients who demonstrated ≥ 25 % tumor shrinkage continued to take tivozanib , and 118 patients with less than 25 % tumor change were r and omly assigned to receive tivozanib or a placebo in a double-blind manner ; patients with ≥ 25 % tumor growth were discontinued . Primary end points included safety , the objective response rate ( ORR ) at 16 weeks , and the percentage of r and omly assigned patients who remained progression free after 12 weeks of double-blind treatment ; secondary end points included progression-free survival ( PFS ) . RESULTS Of 272 patients enrolled onto the study , 83 % of patients had clear-cell histology , 73 % of patients had undergone nephrectomy , and 54 % of patients were treatment naive .  The ORR after 16 weeks of tivozanib treatment was 18 % ( 95 % CI , 14 % to 23 % ) . Of the 118 r and omized patients , significantly more patients who were r and omly assigned to receive double-blind tivozanib remained progression free after 12 weeks versus patients who received the placebo ( 49 % v 21 % ; P = .001 ) . Throughout the study , the ORR was 24 % ( 95 % CI , 19 % to 30 % ) , and the median PFS was 11.7 months ( 95 % CI , 8.3 to 14.3 months ) in the overall study population . The most common grade 3 and 4 treatment-related adverse event was hypertension ( 12 % ) . CONCLUSION Tivozanib was active and well tolerated in patients with advanced RCC . These data support additional development of tivozanib in advanced RCC 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 BACKGROUND Cediranib is a highly potent vascular endothelial growth factor ( VEGF ) signalling inhibitor with activity against VEGF receptors 1 , 2 and 3 . This Phase II , r and omised , double-blind , parallel-group study compared the efficacy of cediranib with placebo in patients with metastatic or recurrent clear cell renal cell carcinoma who had not previously received a VEGF signalling inhibitor . METHODS Patients were r and omised ( 3:1 ) to cediranib 45 mg/day or placebo .  The primary objective was comparison of change from baseline in tumour size after 12 weeks of therapy . Secondary objectives included response rate and duration , progression-free survival ( PFS ) and safety and tolerability . Patients in the placebo group could cross over to open-label cediranib at 12 weeks or earlier if their disease had progressed . This study has been completed and is registered with Clinical Trials.gov , number NCT00423332 . FINDINGS Patients ( n=71 ) were r and omised to receive cediranib ( n=53 ) or placebo ( n=18 ) . The primary study outcome revealed that , after 12weeks of therapy , there was a significant difference in mean percentage change from baseline in tumour size between the cediranib ( -20 % ) and placebo ( + 20 % ) arms ( p<0.0001 ) . Eighteen patients ( 34 % ) on cediranib achieved a partial response and 25 ( 47 % ) experienced stable disease .  Cediranib treatment prolonged PFS significantly compared with placebo ( hazard ratio (HR)=0.45 , 90%confidence interval : 0.26 - 0.76 , p=0.017 ; median PFS 12.1 versus 2.8 months ) . The most common adverse events in patients receiving cediranib were diarrhoea ( 74 % ) , hypertension ( 64 % ) , fatigue ( 58 % ) and dysphonia ( 58 % ) . INTERPRETATION Cediranib monotherapy demonstrated significant evidence of antitumour activity in patients with advanced renal cell carcinoma . The adverse event profile was consistent with previous studies of cediranib 45 mg Background : Since PI3K/AKT/mTOR pathway activation diminishes the effects of hormone therapy , combining aromatase inhibitors ( anatrozole ) with mTOR inhibitors ( everolimus ) was investigated . Patients and Methods : We evaluated anastrozole and everolimus in 55 patients with metastatic estrogen ( ER ) and /or progesterone receptor (PR)-positive breast and gynecologic tumors . Endpoints were safety , antitumor activity and molecular correlates . Results : Full doses of anastrozole ( 1 mg PO daily ) and everolimus ( 10 mg PO daily ) were well tolerated . Twelve of 50 evaluable patients ( 24 % ) ( median = 3 prior therapies ) achieved stable disease ( SD ) ≥ 6 months/partial response (PR)/complete response ( CR ) ( n = 5 ( 10 % ) with PR/CR ) : 9 of 32 ( 28 % ) with breast cancer ( n=5 ( 16 % ) with PR/CR ) ; 2 of 10 ( 20 % ) , ovarian cancer ; and 1 of 6 ( 17 % ) , endometrial cancer . Six of 22 patients ( 27 % ) with molecular alterations in the PI3K/AKT/mTOR pathway achieved SD ≥ 6 months/PR/CR . Six of 8 patients ( 75 % ) with SD ≥ 6 months/PR/CR with molecular testing demonstrated at least one alteration in the PI3K/AKT/mTOR pathway : mutations in PIK3CA ( n=3 ) and AKT1 ( n=1 ) or PTEN loss ( n=3 ) . All three responders ( CR ( n = 1 ) ; PR ( n=2 ) ) who had next generation sequencing demonstrated additional alterations : amplifications in CCNE1 , IRS2 , MCL1 , CCND1 , FGFR1 and MYC and a rearrangement in PRKDC . Conclusions : Combination anastrozole and everolimus is well tolerated at full approved doses , and is active in heavily-pretreated patients with ER and /or PR-positive breast , ovarian and endometrial cancers . Responses were observed in patients with multiple molecular aberrations . Clinical Trails Included : 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  
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Compared with placebo and IFN-α , single vascular epithelial growth factor ( receptor ) tyrosine kinase inhibitor and mammalian target of rapamycin agent ( VEGF(r)-TKI & mTOR inhibitor ) were associated with improved PFS , improved OS and higher ORR , respectively .
Comparing sorafenib combination vs sorafenib , there was no significant difference with regard to PFS and OS , but with a higher ORR .
Comparing single or combination VEGF(r)-TKI & mTOR inhibitor vs BEV + IFN-α , there was no significant difference with regard to PFS , OS , or ORR .
Our network ITC meta- analysis also indicated a superior PFS of axitinib and everolimus compared to sorafenib .
Our data suggest that targeted therapy with VEGF(r)-TKI & mTOR inhibitor is associated with superior efficacy for treating advanced RCC with improved PFS , OS and higher ORR compared to placebo and IFN-α .
In summary , here we give a comprehensive overview of current targeted therapies of advanced RCC that may provide evidence for the adequate targeted therapy selecting