approximately 20%-30% of patients are diagnosed with metastatic disease , and 70%-80% of patients are presented with localized or locally advanced disease at the time of diagnosis , which is potentially curable by radical surgical resection alone . among patients who undergo radical resection for localized disease , an understanding of the pathogenesis of rcc at the molecular level , and randomized clinical trials , have established the standard role of the orally administered vascular endothelial growth factor receptor and platelet derived growth factor receptor inhibitor sunitinib for the treatment of advanced rcc . clinical trials are the standard way to evaluate the efficacy of new investigational therapies [ 5 - 7 ] . in various types of cancer ( e.g. , melanoma , ovarian cancer , lung cancer ) , data suggests that there exist a  trial effect , ' whereby clinical trials participants may have an improved outcome simply by participating in a clinical trial itself [ 5 - 10 ] . positive effects of clinical trials participation may include improved routine care and treatment delivery , quality control , and close observation , leading to better patient compliance and clinician practice . the effect of clinical trial participation on the outcome of treatment in metastatic rcc is poorly defined . this knowledge would be important , as treatment options and clinical trials with targeted therapies for patients with metastatic rcc have significantly expanded in recent years . thus , we aimed to study the effect of clinical trial participation on the outcome of metastatic rcc patients treated with sunitinib . we reviewed the records of patients ( unselected cohort , international multicenter database ) with evidence of metastatic rcc , who were treated with sunitinib between february 1 , 2004 , and december 31 , 2013 , in six centers across two different countries : the united states ( sidney kimmel comprehensive cancer center at johns hopkins , baltimore , md ) and israel ( institute of oncology , meir medical center , kfar saba ; department of oncology , asaf harofe medical center , zerifin ; department of oncology , rambam medical center , haifa ; department of oncology , sheba medical center , tel hashomer ; department of oncology , soroka university medical center , beer - sheva ) . patients treated with sunitinib within clinical trials were identified and individually matched by clinicopathologic factors to patients treated with sunitinib as standard therapy out of a clinical trial . patient data were retrospectively and personally collected by the investigator d.k . from electronic medical records and paper charts , including the following baseline clinical characteristics and known prognostic factors [ 12 - 19 ] : age , sex , pretreatment smoking status ( active versus past / never ) , histology ( clear cell versus non clear cell ) , past nephrectomy , the time interval from initial diagnosis to sunitinib treatment initiation , prior systemic therapies , number of metastases sites , presence of lung / liver / bone metastases , eastern cooperative oncology group ( ecog ) performance status , hemoglobin level , corrected ( for albumin ) calcium level , pre - treatment neutrophil to lymphocyte ratio ( nlr ) , sunitinib induced hypertension , and sunitinib dose reduction or treatment interruption . data on the concomitant use of medications , including angiotensin system inhibitors ( angiotensin converting enzyme inhibitors and angiotensin ii receptor blockers ) and bisphosphonates , was gathered from patients electronic medical records and paper charts , pharmacy records , and by contacting patients and other treating physicians as needed . the outcome data was last updated on december 31 , 2013 , including the objective response rate , progression free survival ( pfs ) , and overall survival ( os ) . patients who did not progress or die by december 31 , 2013 were censored in pfs analysis or os analysis , respectively . sunitinib was administered orally , usually at a starting dose of 50 mg once daily , in 6-week cycles consisting of 4 weeks of treatment followed by 2 weeks without treatment . on treatment dose reduction or treatment interruption were done for the management of adverse events , depending on their type and severity , in accordance to the standard guidelines . treatment was continued until evidence of disease progression on scans , unacceptable adverse events , or death . patient follow - up generally consisted of regular physical examinations and laboratory assessments ( hematologic and serum chemical measurements ) , every 4 - 6 weeks , and imaging studies performed every 12 - 18 weeks . for the evaluation of response , the response evaluation criteria in solid tumors ( recist ) ver . 1.1 was applied . in patients with only bone metastases , only complete response , stable disease , or progressive disease were noted , not partial response . the response was assessed by independent radiologists and treating physicians ( while the patients were on treatment in each center , as part of standard patient follow - up ) . pfs was defined as the time from the initiation of sunitinib treatment until evidence of disease progression on scans or death of any cause . overall survival was defined as the time from the initiation of sunitinib treatment to death of any cause . patients in the groups of clinical trials participants and non - participants were individually matched by age , sex , rcc histology , prior nephrectomy , prior systemic therapy , sunitinib induced hypertension , sunitinib dose reduction / treatment interruption , the use of angiotensin system inhibitors , heng risk , and pretreatment nlr . clinicopathologic characteristics and response rate were compared between clinical trials participants and non - participants , by chi - square test or fisher 's exact test for nominal data , and two - sample t test ( or mann - whitney non - parametric test ) for continuous measures . in all tests , cox proportional hazards regression model was used for comparison of pfs and os between the two groups . furthermore , to determine if participation in a clinical trial is independently associated with treatment outcome , a univariate analysis ( unadjusted ) of association between each clinicopathologic factor and clinical outcome was performed for the entire patient cohort , using logistic regression for response rate and cox regression model for survival outcomes ( pfs and os ) . factors with significant association in the univariate analysis were included in multivariate cox proportional hazards regression model to determine their independent effects . pfs and os times ( probability and median ) were estimated from kaplan - meier curve . the research was carried out in accordance with the approval by the institutional review board committee of our institutions . we reviewed the records of patients ( unselected cohort , international multicenter database ) with evidence of metastatic rcc , who were treated with sunitinib between february 1 , 2004 , and december 31 , 2013 , in six centers across two different countries : the united states ( sidney kimmel comprehensive cancer center at johns hopkins , baltimore , md ) and israel ( institute of oncology , meir medical center , kfar saba ; department of oncology , asaf harofe medical center , zerifin ; department of oncology , rambam medical center , haifa ; department of oncology , sheba medical center , tel hashomer ; department of oncology , soroka university medical center , beer - sheva ) . patients treated with sunitinib within clinical trials were identified and individually matched by clinicopathologic factors to patients treated with sunitinib as standard therapy out of a clinical trial . patient data were retrospectively and personally collected by the investigator d.k . from electronic medical records and paper charts , including the following baseline clinical characteristics and known prognostic factors [ 12 - 19 ] : age , sex , pretreatment smoking status ( active versus past / never ) , histology ( clear cell versus non clear cell ) , past nephrectomy , the time interval from initial diagnosis to sunitinib treatment initiation , prior systemic therapies , number of metastases sites , presence of lung / liver / bone metastases , eastern cooperative oncology group ( ecog ) performance status , hemoglobin level , corrected ( for albumin ) calcium level , pre - treatment neutrophil to lymphocyte ratio ( nlr ) , sunitinib induced hypertension , and sunitinib dose reduction or treatment interruption . data on the concomitant use of medications , including angiotensin system inhibitors ( angiotensin converting enzyme inhibitors and angiotensin ii receptor blockers ) and bisphosphonates , was gathered from patients electronic medical records and paper charts , pharmacy records , and by contacting patients and other treating physicians as needed . the outcome data was last updated on december 31 , 2013 , including the objective response rate , progression free survival ( pfs ) , and overall survival ( os ) . patients who did not progress or die by december 31 , 2013 were censored in pfs analysis or os analysis , respectively . sunitinib was administered orally , usually at a starting dose of 50 mg once daily , in 6-week cycles consisting of 4 weeks of treatment followed by 2 weeks without treatment . on treatment dose reduction or treatment interruption were done for the management of adverse events , depending on their type and severity , in accordance to the standard guidelines . treatment was continued until evidence of disease progression on scans , unacceptable adverse events , or death . patient follow - up generally consisted of regular physical examinations and laboratory assessments ( hematologic and serum chemical measurements ) , every 4 - 6 weeks , and imaging studies performed every 12 - 18 weeks . for the evaluation of response , the response evaluation criteria in solid tumors ( recist ) ver . 1.1 was applied . in patients with only bone metastases , only complete response , stable disease , or progressive disease were noted , not partial response . the response was assessed by independent radiologists and treating physicians ( while the patients were on treatment in each center , as part of standard patient follow - up ) . pfs was defined as the time from the initiation of sunitinib treatment until evidence of disease progression on scans or death of any cause . overall survival was defined as the time from the initiation of sunitinib treatment to death of any cause . patients in the groups of clinical trials participants and non - participants were individually matched by age , sex , rcc histology , prior nephrectomy , prior systemic therapy , sunitinib induced hypertension , sunitinib dose reduction / treatment interruption , the use of angiotensin system inhibitors , heng risk , and pretreatment nlr . clinicopathologic characteristics and response rate were compared between clinical trials participants and non - participants , by chi - square test or fisher 's exact test for nominal data , and two - sample t test ( or mann - whitney non - parametric test ) for continuous measures . in all tests , cox proportional hazards regression model was used for comparison of pfs and os between the two groups . furthermore , to determine if participation in a clinical trial is independently associated with treatment outcome , a univariate analysis ( unadjusted ) of association between each clinicopathologic factor and clinical outcome was performed for the entire patient cohort , using logistic regression for response rate and cox regression model for survival outcomes ( pfs and os ) . factors with significant association in the univariate analysis were included in multivariate cox proportional hazards regression model to determine their independent effects . pfs and os times ( probability and median ) were estimated from kaplan - meier curve . the research was carried out in accordance with the approval by the institutional review board committee of our institutions . forty - nine patients treated with sunitinib within clinical trials ( nct00083889 , nct00130897 , nct00444314 ) were identified and individually matched , via clinicopathologic factors , to 49 patients treated with sunitinib as the standard therapy out of a clinical trial . clinicopathologic factors used to individually match patients were age ( median , 64 years ) , sex ( male , 67% ) , histology ( clear cell , 86% ; n=42 ) , past nephrectomy ( 92% , n=45 ) , prior systemic therapy ( 16% , n=8 ; including interferone n=5 in clinical trials participants and n=6 in non - participants , or il-2 n=3 in participants and n=2 in non - participants ) , sunitinib induced hypertension ( 45% , n=27 ) , sunitinib dose reduction / treatment interruption ( 41% , n=20 ) , use of angiotensin system inhibitors ( 37% , n=18 ) , heng risk stratification ( favorable 25% , n=12 ; intermediate 59% , n=29 ; poor 16% , n=8 ) , and pre - treatment nlr (  3 in 55% , n=27 ) . the groups were balanced with regard to the presence of lung ( p=0.62)/liver ( p=0.27)/bone ( p=0.67 ) metastases , number of metastatic sites ( p=0.8 ) , smoking status ( p=0.97 ) , presence of sarcomatoid component in tumor histology ( p=0.84 ) , and subsequent lines of therapy ( p=0.7 and p=0.85 for subsequent second and third lines of therapy ) . in clinical trial participants , subsequent second line of therapy included sorafenib ( n=13 ) , bevacizumab ( n=6 ) , and everolimus ( n=5 ) ; moreover , subsequent third line of therapy included everolimus ( n=2 ) , bevacizumab ( n=1 ) , and sunitinib rechallenge ( n=1 ) . in clinical trial non - participants , subsequent second line of therapy included temsirolimus ( n=7 ) , everolimus ( n=5 ) , sorafenib ( n=4 ) , pazopanib ( n=3 ) , and bevacizumab ( n=2 ) ; and subsequent third line of therapy included pazopanib ( n=2 ) , and axitinib ( n=1 ) . in clinical trial participants versus non - participants , objective response was partial response / stable disease 80% ( n=39 ) versus 74% ( n=36 ) , and progressive disease at first imaging evaluation within the first 3 months 20% ( n=10 ) versus 26% ( n=13 ) ( p=0.63 ; odds ratio , 1.2 ) ( table 2 ) . 1 ) was 10 versus 11 months ( hazard ratio [ hr ] , 0.96 ; p=0.84 ) , and median os ( fig . 2 ) 23 versus 24 months ( hr , 0.97 ; p=0.89 ) ( table 2 ) . smoking status ( hr , 3.35 ; p < 0.001 for active vs. never / past smokers ) , heng risk ( hr , 1.23 and 2.5 ; p=0.41 and p=0.005 , for favorable and intermediate versus poor risk , respectively ) , use of angiotensin system inhibitors ( hr , 0.6 for yes vs. no ; p=0.024 ) , past nephrectomy ( hr , 0.41 for yes vs. no ; p=0.014 ) , sunitinib induced hypertension ( hr , 0.57 for yes vs no ; p=0.009 ) , non - clear cell histology ( hr , 2.8 vs. clear cell histology ; p=0.001 ) , and pre - sunitinib treatment nlr > 3 ( hr , 2.5 for > 3 vs.  3 ; p < the status of clinical trial participation ( yes vs. no ) was not associated with pfs ( hr , 1.1 ; p=0.7 ) . smoking status ( hr , 3 ; p < 0.001 for active vs. never / past smokers ) , heng risk ( hr , 1.38 and 2.13 ; p=0.23 and p=0.032 , for favorable and intermediate versus poor risk , respectively ) , past nephrectomy ( hr , 0.4 for yes vs. no ; p=0.012 ) , non - clear cell histology ( hr , 2 vs. clear cell histology ; p=0.023 ) , sunitinib induced hypertension ( hr , 0.59 for yes vs. no ; p=0.019 ) , and pre - sunitinib treatment nlr > 3 ( hr , 1.8 for > 3 vs.  3 ; p=0.009 ) were individually associated with os . status of clinical trial participation ( yes vs. no ) was not associated with pfs ( hr , 1.15 ; p=0.48 ) . factors independently associated with pfs were smoking status ( hr , 2.18 ; p=0.009 , for active vs. never / past smokers ) , non - clear cell histology ( hr , 3 vs. clear cell histology ; p=0.008 ) , use of angiotensin system inhibitors ( hr , 0.56 for yes vs. no ; p=0.03 ) , and pre - treatment nlr > 3 ( hr , 1.95 for > 3 vs.  3 ; p=0.015 ) . factors that were independently associated with os were smoking status ( hr , 2.9 ; p=0.001 , for active vs never / past smokers ) , non - clear cell histology ( hr , 2.1 vs. clear cell histology ; p=0.032 ) , and pre - treatment nlr > 3 ( hr , 1.4 for > 3 vs.  3 ; p=0.02 ) . forty - nine patients treated with sunitinib within clinical trials ( nct00083889 , nct00130897 , nct00444314 ) were identified and individually matched , via clinicopathologic factors , to 49 patients treated with sunitinib as the standard therapy out of a clinical trial . clinicopathologic factors used to individually match patients were age ( median , 64 years ) , sex ( male , 67% ) , histology ( clear cell , 86% ; n=42 ) , past nephrectomy ( 92% , n=45 ) , prior systemic therapy ( 16% , n=8 ; including interferone n=5 in clinical trials participants and n=6 in non - participants , or il-2 n=3 in participants and n=2 in non - participants ) , sunitinib induced hypertension ( 45% , n=27 ) , sunitinib dose reduction / treatment interruption ( 41% , n=20 ) , use of angiotensin system inhibitors ( 37% , n=18 ) , heng risk stratification ( favorable 25% , n=12 ; intermediate 59% , n=29 ; poor 16% , n=8 ) , and pre - treatment nlr (  3 in 55% , n=27 ) . the groups were balanced with regard to the presence of lung ( p=0.62)/liver ( p=0.27)/bone ( p=0.67 ) metastases , number of metastatic sites ( p=0.8 ) , smoking status ( p=0.97 ) , presence of sarcomatoid component in tumor histology ( p=0.84 ) , and subsequent lines of therapy ( p=0.7 and p=0.85 for subsequent second and third lines of therapy ) . in clinical trial participants , subsequent second line of therapy included sorafenib ( n=13 ) , bevacizumab ( n=6 ) , and everolimus ( n=5 ) ; moreover , subsequent third line of therapy included everolimus ( n=2 ) , bevacizumab ( n=1 ) , and sunitinib rechallenge ( n=1 ) . in clinical trial non - participants , subsequent second line of therapy included temsirolimus ( n=7 ) , everolimus ( n=5 ) , sorafenib ( n=4 ) , pazopanib ( n=3 ) , and bevacizumab ( n=2 ) ; and subsequent third line of therapy included pazopanib ( n=2 ) , and axitinib ( n=1 ) . in clinical trial participants versus non - participants , objective response was partial response / stable disease 80% ( n=39 ) versus 74% ( n=36 ) , and progressive disease at first imaging evaluation within the first 3 months 20% ( n=10 ) versus 26% ( n=13 ) ( p=0.63 ; odds ratio , 1.2 ) ( table 2 ) . 1 ) was 10 versus 11 months ( hazard ratio [ hr ] , 0.96 ; p=0.84 ) , and median os ( fig . 2 ) 23 versus 24 months ( hr , 0.97 ; p=0.89 ) ( table 2 ) . smoking status ( hr , 3.35 ; p < 0.001 for active vs. never / past smokers ) , heng risk ( hr , 1.23 and 2.5 ; p=0.41 and p=0.005 , for favorable and intermediate versus poor risk , respectively ) , use of angiotensin system inhibitors ( hr , 0.6 for yes vs. no ; p=0.024 ) , past nephrectomy ( hr , 0.41 for yes vs. no ; p=0.014 ) , sunitinib induced hypertension ( hr , 0.57 for yes vs no ; p=0.009 ) , non - clear cell histology ( hr , 2.8 vs. clear cell histology ; p=0.001 ) , and pre - sunitinib treatment nlr > 3 ( hr , 2.5 for > 3 vs.  3 ; p < the status of clinical trial participation ( yes vs. no ) was not associated with pfs ( hr , 1.1 ; p=0.7 ) . smoking status ( hr , 3 ; p < 0.001 for active vs. never / past smokers ) , heng risk ( hr , 1.38 and 2.13 ; p=0.23 and p=0.032 , for favorable and intermediate versus poor risk , respectively ) , past nephrectomy ( hr , 0.4 for yes vs. no ; p=0.012 ) , non - clear cell histology ( hr , 2 vs. clear cell histology ; p=0.023 ) , sunitinib induced hypertension ( hr , 0.59 for yes vs. no ; p=0.019 ) , and pre - sunitinib treatment nlr > 3 ( hr , 1.8 for > 3 vs.  3 ; p=0.009 ) were individually associated with os . status of clinical trial participation ( yes vs. no ) was not associated with pfs ( hr , 1.15 ; p=0.48 ) . factors independently associated with pfs were smoking status ( hr , 2.18 ; p=0.009 , for active vs. never / past smokers ) , non - clear cell histology ( hr , 3 vs. clear cell histology ; p=0.008 ) , use of angiotensin system inhibitors ( hr , 0.56 for yes vs. no ; p=0.03 ) , and pre - treatment nlr > 3 ( hr , 1.95 for > 3 vs.  3 ; p=0.015 ) . factors that were independently associated with os were smoking status ( hr , 2.9 ; p=0.001 , for active vs never / past smokers ) , non - clear cell histology ( hr , 2.1 vs. clear cell histology ; p=0.032 ) , and pre - treatment nlr > 3 ( hr , 1.4 for > 3 vs.  3 ; p=0.02 ) . in the present study , we did not find a  clinical trial effect in patients with metastatic rcc treated with sunitinib . the outcome of clinical trial participants was similar to that of matched patients treated out of a trial , in terms of objective response , pfs , and os . furthermore , in a univariate - multivariate analysis of the entire patient cohort ( trial participants plus non - participants ) , the status of clinical trial participation was not associated with treatment outcome . a positive effect of clinical trial participation on treatment outcome , may be explained by multiple factors , including a protocol effect ( the way therapy is given ) , care effect ( incidental aspects of care ) , hawthorne effect ( changes in health care practitioners and patients behavior due to the knowledge that they are under monitoring ) , placebo effect , treatment ( per clinical trial ) in high - volume centers ( per clinical trial ) versus non - academic institutions ( i.e. , participation in clinical trials may represent a quality characteristic of medical centers . thus , healthcare systems that are active in clinical trials may deliver better outcomes for patients than healthcare systems that are inactive in trials ) [ 9 - 11,20 ] . another potential association between clinical trial participation and outcome may also arise if clinicians who tend to recruit to trials also tend to be more competent clinicians . however , some studies found only a weak evidence to suggest that clinical trials participation leads to a positive effect on the outcome of participants [ 8,9,20 - 22 ] . furthermore , other studies found a trial effect only when the investigational treatment arm of a clinical trial was more efficacious than the standard treatment arm . moreover , improvement in outcomes of patients participating in clinical trials , as reported by some studies , might be related to bias from methodological difficulties as data collection , i.e. , retrospective analysis , patient selection ( e.g. , exclusion of patients with coexisting medical conditions ) , a better follow - up of patients treated per clinical trials than out of trials , and failure to publish studies reporting negative trial effects . various reasons might be put forward to explain the present study findings , of similar outcomes between clinical trial participants and non - participants . it is possible that institutional standardization of care ( e.g. , regular follow - up by a dedicated nurse who specialized in the management of sunitinib toxicity ) , may provide the same benefit as treatment , thus eliminating the potential for the participation effects . second , our patients were treated with an oral targeted agent . in most studies reporting clinical trial effect , patients were treated with intravenous chemotherapy and radiation therapy . to the best of our knowledge , the effect of clinical trial participation on the outcome of modern targeted therapies is poorly defined . finally , some data suggests that when stratified by tumor type , the beneficial effect of trial enrollment may be seen only in selected types , such as breast , lung and colon cancer , and may not be seen in other types , such as melanoma , pancreatic and hepatobiliary cancers . first , this is a multicenter retrospective study that represents an unselected heterogeneous cohort of patients that were treated with sunitinib , including all histologic variants of rcc , and patients who were treatment nave and those with a history of prior therapy . moreover , our data do not exclude the possibility of a trial effect at other institutions . nonetheless , the outcome of the present study patient population ( i.e. , median pfs of 10 - 11 months , and median os of 23 - 24 months ) is similar to the previously published data on patients with metastatic rcc that are treated with sunitinib . second , we are unable to exclude the possibility that unequal distribution of unidentified clinicopathologic parameters in our patient cohort may have biased the observed results . thus , our study might have been underpowered to show a difference in the outcome . other clinicopathologic factors , including status of clinical trial participation , that were not found to be significantly associated with disease progression in the present study might have been important in a larger patient cohort . fourth , whether our findings are specific to sunitinib or generalizable to other tyrosine kinase inhibitors is not known . despite these limitations , our clinical observation on the status of clinical trial participation does not impact the outcome of sunitinib treatment in metastatic rcc an may contribute to treatment decisions , patient selection , and clinical trials design . given the above evidence , discussion between clinicians and mrcc patients about participation in a clinical trial should focus on the improvement of future therapy , and not the direct benefit of research participation . physicians should not imply a survival benefit when counseling metastatic rcc patients about entering clinical trials . further prospective studies may be warranted , to test and confirm our hypothesis generating observation in larger patient cohorts , to define the association between clinical trial participation and outcome in different subgroups of patients ( e.g. , according to risk by prognostic models , clear cell versus non - clear cell histology , and first line versus advanced line treatment ) . we investigated the effect of clinical trial participation on outcome of patients with mrcc who were treated with sunitinib . after accounting for other clinicopathologic factors , we were unable to show that participation in a clinical trial may in itself provide an outcome advantage to these patients . the present study may improve confidence that the trial treatment effects will translate to the real - world setting . discussion between clinicians and mrcc patients regarding participation in a clinical trial should focus on the improvement of future therapy rather than the direct outcome of research participation .