***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 OBJECTIVE Sorafenib ( Nexavar ) is an oral multi-kinase inhibitor that targets tumor growth and angiogenesis . This phase II study investigated efficacy , safety , and pharmacokinetics of sorafenib in Japanese patients with advanced renal cell carcinoma ( RCC ) . METHODS Nonr and omized , open-label study in Japanese patients with metastatic renal cell carcinoma who had received nephrectomy and failed > /=1 cytokine-containing therapy .  The primary endpoint was response rate . Patients received sorafenib 400 mg twice daily ( b.i.d . ) on a continuous dosing schedule . RESULTS A total of 129 patients ( median age 63 years ) were valid for intention-to-treat analyses . Confirmed partial responses were observed in 16 ( 12.4 % ) patients , and investigators assessed that 19 ( 14.7 % ) of the patients achieved a partial response . Stable disease was reported in 93 ( 72.1 % ) patients , and 103 ( 80.5 % ) patients had tumor shrinkage . Median progression-free survival was 224 days and the 25th percentile of overall survival was estimated at 288 days . The most frequently occurring drug-related adverse events ( any grade ) were elevated lipase ( 56 % ) , h and -foot skin reaction ( 55 % ) , alopecia ( 39 % ) , increased amylase ( 38 % ) , rash/desquamation ( 37 % ) , and diarrhea ( 34 % ) . A total of 14 ( 10.7 % ) patients had serious sorafenib-related adverse events , including one adverse event of worst grade 5 ( dyspnea occurred 35 days after the last dose of study medication ) . The C(trough , steady state ) values in RCC patients ( n = 63 ) receiving sorafenib 400 mg b.i.d . were similar to those obtained from a Japanese phase I study involving patients with mixed solid tumors . CONCLUSION Sorafenib showed encouraging efficacy and was well tolerated in Japanese patients with metastatic RCC 5099 Background : So is an orally active multikinase inhibitor with a well documented activity in advanced RCC . IL-2 is a pleiotropic cytokine with antitumoral activity depending on dose and schedule . The aim of the study is to evaluate the activity and the safety of So and IL-2 association compared to So alone . METHODS In this multicenter , r and omized , open label , phase II study , 128 previously untreated metastatic RCC patients ( pts ) were r and omized to receive 400 mg of So , orally given twice daily continuously , in combination with IL-2 , 4.5 MIU administered subcutaneously , five times a week for six consecutive weeks any eight weeks ( arm A ) , or So alone ( arm B ) at the same dose . Therapy continued until progression of disease or unacceptable toxicity . The primary end point was progression free survival ( PFS ) and the secondary endpoints were response rate , safety and overall survival .  Eligible pts had histological diagnosis of RCC , ECOG 0 - 2 , no brain metastases , measurable disease and any Motzer 's score . Pts were stratified according to different histotypes and Motzer 's score . RESULTS All pts were enrolled from October 2006 to February 2008 .  Response rates ( all partial responses , PR ) were 23 % and 10 % in arm A and B respectively . Overall disease control rates ( PR + stable disease SD ) were 81 % versus 74 % . Tumour shrinkage was reported in 52 % and 34 % of arm A and B therapies respectively . Median PFS was 38 weeks ( range 6 - 104 + ) for So + IL-2 and 30 weeks ( range 6 - 102 + ) for So alone . PFS at 1 year was 31 % in the combination therapy versus 22 % in arm B. The most common adverse events ( AEs ) were asthenia , h and foot syndrome , hypertension , fever , diarrhoea and mucositis . AE were usually low or moderate in severity and always reversible and manageable . Grade 3 - 4 AE were reported in 33 % and 22 % in arm A and B , respectively . CONCLUSIONS The safety and efficacy data suggest that the association So + IL-2 is safe and feasible and , compared to So alone , improves tumour shrinkage , disease control rate and PFS . [ Table : see text ] 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 ] . ) To assess the response rate and safety of sorafenib in different sub population s of patients with advanced renal cell carcinoma ( RCC ) 4557 Background : VEGFR TKIs show activity in patients ( pts ) with metastatic RCC ; however , their activity in the adjuvant setting is unknown . VEGFR TKI-targeted tx of pts with advanced cancer induces changes in circulating proangiogenic cyts ; the source of these molecules is unknown . In order to see if these changes were host dependent we performed plasma analysis of circulating cyts in pts treated with  adjuvant sunitinib ( Su ) , sorafenib ( So ) or placebo  ( P ) on ECOG E2805 . METHODS 1,943 pts were enrolled in E2805 , study of adjuvant tx in pts with resected RCC . Pts were r and omized to Su 50 mg po qd for 4 of 6 wks ; So 400 mg po BID qd ; or P ) . Plasma was collected at the start of tx ( 4 - 12 wks post nephrectomy ) and at either 4 or 6 wks into tx . Levels of circulating VEGF , bFGF , sFLT1 , and placental growth factor ( PlGF ) were measured by multiplex array ( Meso-Scale Disc . ) . Mixed models were used to estimate log-transformed cyt levels in each group , adjusting for effects due to plate and processing day and accounting for within-subject correlation . P values are from model-based tests of fixed effects ( F tests ) . RESULTS 1,416 sample s from 352 pts were included ; table shows results in ng/ml . VEGF levels increased from baseline to post-cycle 1 in Su pts ( measured at 4 wks ) and in So pts , and remained stable in P pts . No consistent patterns of change between arms for bFGF , sFLT or PlGF were seen , after adjusting for processing effects . CONCLUSIONS Of cyts measured , the most consistent changes were seen in VEGF levels . Treatment with Su and So increased VEGF levels in pts with no evidence of cancer , signifying that levels are mediated at least in part by the host . No difference from baseline to post-tx among Su patients with sample s drawn at 6 wks was observed , suggesting that changes are reversible . On the contrary , So-treated pts maintained elevated VEGF levels at wk 6 ( 2 wks off tx ) , consistent with the continuous dosing schedule . Further study of the relationship among VEGF levels , tx outcomes and side effects is warranted . [ Table : see text ] Purpose Immunotherapy ( IL-2 and INF-α ) was the treatment of choice for advanced renal cell carcinoma ( RCC ) until antiangiogenic therapy with tyrosin kinase inhibitors was developed in the early 2000s . This clinical trial explored the efficacy and toxicity of sequential treatment of IL-2 plus INF-α followed by sorafenib . Methods Eligibility criteria included measurable , non-resectable , histologically confirmed predominantly clear cell RCC , no prior systemic treatment , and ECOG PS 0–2 . The treatment regimen was a 6-week cycle of subcutaneous IL-2 at 9 × 106 IU on days 1–6 of weeks 1 , 2 , 4 and 5 plus s.c . INF-α at 6 × 106 IU on days 1 , 3 and 5 of weeks 1–6 . Responders received 6 additional weeks of this regimen . All patients received oral sorafenib ( 400 mg bid ) after immunotherapy until disease progression . The primary endpoint was progression-free survival . Results Forty-one patients were enrolled , median age 57 years . ECOG was 0/1 in 17/20 patients , 35 patients had prior nephrectomy and 18 patients pure clear cell cancer . Median PFS was 7.4 months ( 95 % CI 6.5–13.1 ) and OS was 16.6 months ( 95 % CI not reached ) . In 36 patients evaluable for response , ORR was 44.4 % and control rate was 94.4 % . Most adverse events 
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The PFS appeared shorter in second- vs. first-line treatment , consistent with the more advanced tumor status in the second-line setting .
These variances may be attributable to increased recognition of HFSR , or potentially differences in dose adjustments , that could be consequences of increased familiarity with sorafenib usage .
Conclusions Collectively , more recent experiences using sorafenib in RCC are consistent with results reported for TARGET with no marked changes of response endpoints or new safety signals observed