***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: PURPOSE To define outcome data and prognostic criteria for patients with metastatic renal cell carcinoma ( RCC ) treated with interferon-alfa as initial systemic therapy . The data can be applied to design and interpretation of clinical trials of new agents and treatment programs against this refractory malignancy . PATIENTS AND METHODS Four hundred sixty-three patients with advanced RCC administered interferon-alpha as first-line systemic therapy on six prospect i ve clinical trials were the subjects of this retrospective analysis . Three risk categories for predicting survival were identified on the basis of five pretreatment clinical features by a stratified Cox proportional hazards model . RESULTS The median overall survival time was 13 months . The median time to progression was 4.7 months . Five variables were used as risk factors for short survival : low Karnofsky performance status , high lactate dehydrogenase , low serum hemoglobin , high corrected serum calcium , and time from initial RCC diagnosis to start of interferon-alpha therapy of less than one year . Each patient was assigned to one of three risk groups : those with zero risk factors ( favorable risk ) , those with one or two ( intermediate risk ) , and those with three or more ( poor risk ) . The median time to death of patients deemed favorable risk was 30 months . Median survival time in the intermediate-risk group was 14 months . In contrast , the poor-risk group had a median survival time of 5 months . CONCLUSION Progression-free and overall survival with interferon-alpha treatment can be compared with new therapies in phase II and III clinical investigations . The prognostic model is suitable for risk stratification of phase III trials using interferon-alpha as the comparative treatment arm Objective : To report side effects seen in a clinical cohort of patients aged > 65 years with rheumatoid arthritis ( RA ) treated with the tumor necrosis factor-α TNF-α blocker etanercept  and to compare the side effects rate with patients aged ≤65 years . Methods : All patients with RA that started etanercept and who were referred to our rheumatology unit from November 2005 to March 2009 were included in this study and prospect ively followed to collect side effects related to therapy . Results : One hundred three patients were enrolled : 41 ( 37 females , 4 males ) aged > 65 years and 62 ( 40 females , 22 males ) aged < 65 years . In the patients aged > 65 years , the safety profile ( defined as rate of side effects ) of etanercept was similar to that in patients aged ≤65 years ( P > 0.05 ) and the survival curves between the groups were similar ( P > 0.05 ) . Conclusions : In our three-year experience , the anti-TNFα agent etanercept has been well tolerated and safe in elderly patients .  The risk of side effects in these patients was no greater than in subjects aged ≤65 years . However , such inhibitors are associated with various and numerous side effects and elderly patients with RA should be carefully monitored to limit the risk of side effects during anti-TNFα therapy as much as possible 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 Background The development of novel chemotherapeutic agents in colorectal cancer has improved survival . Following initial response to chemotherapeutic strategies many patients develop refractory disease . This poses a significant challenge common to many cancer subtypes . Newer agents such as Bevacizumab have successfully targeted the tyrosine kinase receptor epidermal growth factor receptor in metastatic colorectal cancer . Human epidermal growth factor receptor-2 is another member of the tyrosine kinase receptor family which has been successfully targeted in breast cancer . This may play a role in colorectal cancer . We conducted a clinicopathological study to determine if overexpression of human epidermal growth factor receptor-2 is a predictor of outcome in a cohort of patients with colorectal cancer . Methods Clinicopathological data and paraffin-embedded specimens were collected on 132 consecutive patients who underwent colorectal resections over a 24-month period at Mayo General Hospital . Twenty-six contained non-malignant disease . Her-2/neu protein overexpression was detected using immunohistochemistry ( IHC ) . The HER-2 4B5 Ventana monoclonal antibody was used . Fluorescent insitu hybridisation ( FISH ) was performed using INFORM HER-2/Neu Plus . Results were correlated with established clinical and pathological predictors of outcome including TNM stage . Statistical analysis was performed using SPSS version 11.5 . Results 114 were HER-2/Neu negative using IHC , 7 showed barely perceptible positivity ( 1 + ) , 9 showed moderate staining ( 2 + ) and 2 were strongly positive ( 3 + ) . There was no correlation with gender , age , grade , Dukes ' stage , TNM stage , time to recurrence and 5-year survival ( p > 0.05 ) . FISH was applied to all 2 + and 3 + cases as well as some negative cases selected at r and om . Three were amplified ( 2 were 3 + and 1 was 2 + ) . Similarly , HER-2 gene overexpression did not correlate with established prognostic indicators . Conclusion HER-2 protein is over expressed in 11 % of colorectal cancer patients . The gene encoding HER-2 is amplified in 3 % of cases . Overexpression of HER-2 is not a predictor of outcome . However , patients who over express HER-2 may respond to Herceptin therapy LBA4 Background : Temsirolimus ( TEMSR , CCI-779 ) is a specific inhibitor of mTOR , a signaling protein that regulates cell growth and angiogenesis . In a single-agent , phase 2 study , TEMSR administration to heavily pretreated patients ( pts , n = 111 ) with adv RCC result ed in a median overall survival ( OS ) of 15.0 mos ( Atkins et al , J Clin Oncol 2004 ) . Retrospectively , 49 pts were categorized in a poor-risk group ( Motzer et al , J Clin Oncol 2002 ) . The TEMSR-treated pts in this group had a 1.7-fold longer median OS than the first-line , IFN-treated , poor-risk group reported by Motzer et al. In a phase 1 study , the maximum tolerated dose of the combination of TEMSR + IFN in adv RCC pts was TEMSR 15 mg intravenously ( IV ) once/wk + IFN 6 million units ( MU ) subcutaneously ( SC ) 3 times weekly ( TIW ) ( Smith et al , Proc ASCO 2004 ) . Thus , this phase 3 study in first-line , poor-risk adv RCC pts was initiated in July 2003 . METHODS Pts with adv RCC and no prior systemic therapy were enrolled in this open-label study if they had ≥3 of 6 risk factors ( the 5 Motzer criteria and > 1 metastatic disease site ) . Pts were r and omized ( 1:1:1 ) to arm 1 , IFN up to 18 MU SC TIW ; arm 2 , TEMSR 25 mg IV once/wk ; or arm 3 , TEMSR 15 mg IV once/wk + IFN 6 MU SC TIW . The primary study endpoint was OS ; the study was powered to compare the TEMSR arms with the IFN arm . RESULTS We report 20 Mar 2006 preliminary data from an interim analysis performed by the IDMC . Of the 626 pts enrolled , 442 deaths occurred . Patients treated with TEMSR had a statistically longer survival than those treated with IFN ( Table ) . OS of patients treated with IFN and TEMSR + IFN were not statistically different . The 3 most frequently occurring adverse events ≥gr 3 were asthenia ( arm 1 : arm 2 : arm 3 , 27 % : 12 % : 30 % pts ) , anemia ( 24 % : 21 % : 39 % pts ) , and dyspnea ( 8 % : 9 % : 11 % pts ) . CONCLUSIONS Single-agent TEMSR significantly increases the OS of first-line , poor-risk adv RCC pts compared with IFN , with an acceptable safety profile . [ Table : see text ] [ Table : see text ] Sir , We thank you for providing us the opportunity to respond to the Letter to the Editor received by your office in response to our article ‘ Sunitinib and bevacizumab for first-line treatment of metastatic renal cell carcinoma : a systematic review and indirect comparison of clinical effectiveness ' ( Thompson Coon et al , 2009 ) . We are pleased that Professor Mickisch recognises the need for and importance of indirect treatment comparisons in the absence of head-to-head comparisons and welcome a debate on the relative merits of indirect treatment comparison methods . It appears that some of the comments outlined by Professor Mickisch stem from a misunderst and ing of the methods used in our analysis . Ideally we would have given a more detailed account in the paper , but owing to restrictions in the length of the article we chose to rely on the cited reference ( Ades , 2003 ) to provide a fuller description of the methods used . Our analysis was mainly conducted within the Bayesian framework and as such issues relating to frequentist hypothesis testing are not applicable . Our analysis compared the reported differences ( hazard ratios ) between the three treatments rather than comparing the absolute effects of sunitinib with those of bevacizumab plus IFN and those of IFN alone . Accordingly , it is important to clarify that we did not use a one-sided t-test to calculate the P-value , as inferred by Professor Mickisch . We acknowledge that the language used in describing the output from the MCMC as a one-sided P-value may give rise to some interpretation issues for an audience who are more familiar with frequentist hypothesis testing than Bayesian analysis . The P-value obtained from the MCMC – although regarded as equivalent to that obtained from a one-sided test – is in reality a direct estimate of the probability that one treatment is better than another . It is one of the advantages of the Bayesian approach that it enables intuitive probability statements to be made about propositions ; in this case , 0.0272 is an estimate of the probability that bevacizumab provides superior PFS gain to sunitinib . As a result , within the context of our analysis , it would have been neither possible nor desirable to adopt the methods suggested by Professor Mickisch , which relate solely to the frequentist paradigm . In terms of the number of simulations used in our analysis , we are unaware of any references suggesting that simulation numbers should be as low as 2000 iterations in an MCMC and we would be interested in the source of Professor Mickisch 's comments . It is important to clarify that we were not simulating individual patient experiences but rather repeatedly sampling the differences between treatments in each of the uncertain distributions ( i.e. , our analysis was at the level of a cohort of patients as reflected in trial results ) . Accordingly , caution s that apply to , for example , bootstrap sampling of individual patient data are not applicable in this instance . Increasing the number of simulations in an MCMC will produce a more accurate estimate ( with less possibility of the outputs being distorted by outlying or extreme simulations ) , but will not result in spurious certainty ( in other words , the posterior distribution will become smoother , but not narrower ) . Notwithst and ing the relevance of guidance from the Canadian Agency for Drugs and Technologies in Health ( CADTH ) to this work , we do not share Professor Mickisch 
    Output:
    
In patients with clear cell renal cancers who had failed prior cytokine therapy , oral sorafenib gives a better quality of life than placebo as well as improved chance of being free of disease progression ; overall survival may have improved but is hard to evaluate because of crossover of placebo-assigned patients after the study closed to accrual ( Escudier 2007a ) .
Based on less than a decade of experience , some targeted agents with specified molecular targets have demonstrated clinical ly useful benefits over the previous st and ard of care for patients with advanced renal cancer .