worldwide , metastases are observed in 20%-30% of patients with an initial diagnosis of renal cell carcinoma ( rcc ) , even in those with localized rcc who undergo curative nephrectomy during follow - up . in the immunotherapy ( it )
era , cytokine - mediated it using interferon alpha ( ifn- ) or interleukin-2 ( il-2 ) or both were the first - line systemic treatment modalities for metastatic rcc ( mrcc ) .
further attempts to augment cytokine - based it activity ( e.g. , inclusion of vinblastine and 5-fluorouracil [ 5-fu ] chemotherapy ) led to slightly improved objective response rate ( orr ) .
however , the efficacy of such combinations was likely due to the cytokine effect , because the addition of vinblastine did not improve the progression - free survival ( pfs ) or overall survival ( os ) .
the reported median survival time of mrcc in the it era was 12 months and the 2-year survival rate was 10%-20% , mainly due to a low orr of 10%-20% , with long - term durable responses only observed in 5%-7% of patients undergoing high - dose il-2based therapy .
recent advances in understanding of the biology and genetics of rcc have led to the introduction of several novel multi - pathway targeted agents .
clinical trials in treatmentnave mrcc patients conducted in western and asian countries have shown that targeted therapy ( tt ) had superior efficacy when compared with cytokine - based it . in terms of pfs and os , the clinical outcome of patients with mrcc has improved dramatically since the introduction of tt , which has now replaced it as the standard systemic treatment for mrcc . to facilitate prompt management strategies and achieve the optimal therapeutic response
, physicians should be aware of the efficacies and limitations of systemic mono , combinational , and sequential therapies of diverse therapeutic agents for the treatment of mrcc .
however , few large studies comparing the outcome of it and tt in patients with mrcc have been reported , although small comparative studies have been conducted .
the current study assessed the outcome of systemic tt and it administered to a large number of patients with mrcc over a 10-year period at a single korean cancer institution .
data from 262 patients with mrcc treated with systemic agents between 2003 and 2013 were evaluated retrospectively .
patients who were administered it as a systemic therapy between 2003 and 2013 were selected from the prospectively recorded rcc database of the national cancer center hospital , and those administered tt who were treated between 2006 and 2013 were selected .
of the 262 patients , 135 ( 51.5% ) underwent first - line it regimens based on mono or combinational therapy with ifn- , il-2 , 5-fu , or vinblastine . the remaining 127 patients ( 48.5% ) underwent first - line systemic tt .
patients with no follow - up history and who had incomplete rcc treatment histories were excluded .
additional information about the clinical outcomes of 96 patients treated with either tt or it as a sequential second - line systemic therapy was also evaluated .
the choice of it or tt was at the discretion of the treating urologist ( j.c . ) and was based on the patient s histopathology and coverage by the national health insurance system .
combination it comprised different combinations of subcutaneous recombinant human il-2 ( aldesleukin , proleukin , chiron corporation , emeryville , ca ) or recombinant human ifn- ( ifn - alpha-2a , roferon - a , hoffmann - la roche , nutley , nj ) , and intravenous 5-fu ( jw pharm , seoul , korea ) or vinblastine ( united pharm , seoul , korea ) . the triple or quadruple regimens were administered as follows : il-2 , 20 miu / m on days 35 of weeks 1 and 4 , and 5
miu / m il-2 on days 1 , 3 , and 5 of weeks 2 and 3 ; ifn- , 6
miu / m on day 1 of weeks 1 and 4 and on days 1 , 3 , and 5 of weeks 2 and 3 , and 9 miu / m on days 1 , 3 , and 5 of weeks 5 - 8 ; 5-fu , 750 mg / m once weekly during weeks 5 - 8 ; with ( quadruple ) or without vinblastine ( triple ) at 0.1 mg / kg once weekly during weeks 5 - 8 . the dual combination regimen of vinblastine plus ifn- was administered as ifn- at 9
miu / m on days 1 , 3 , and 5 each week , and vinblastine at 0.1 mg / kg every 3 weeks .
all tt was administered orally . for sunitinib , each cycle consisted of 50 mg / day for 4 weeks followed by a 2-week hiatus .
subjects were administered consecutive 10 mg of everolimus once a day per week and 5 mg of axitinib twice a day per week as the second - line tt .
the treatment response was assessed every 4 - 6 weeks for sorafenib , pazopanib , everolimus , and axitinib . during follow - up ,
meticulous history taking , physical examination , routine blood tests , abdominal computed tomography ( ct ) , radionuclide bone scan , simple chest radiography , and/or chest ct , and electrocardiography were performed at regular intervals . in addition , mandatory thyroid function tests and echocardiography were performed in patients scheduled to receive tt .
all responses were evaluated on ct imaging according to the response evaluation criteria in solid tumor ( recist ) ver .
therapeutic responses were assessed at the end of each cycle ( at 8 weeks for the triple and quadruple it regimens ) or every 3 - 4 cycles ( at 9 - 12 weeks for the dual it regimen ) . for tt ,
response was assessed at the end of two cycles and treatment was continued until disease progression .
time to progression and death were assessed using kaplan - meier analysis with the log - rank test .
the orr , pfs , and os of the first- and second - line therapies were assessed according to the systemic agent and the clinical outcomes of sequential treatment with it and tt , and their prognostic stratifications , were also evaluated according to the memorial sloan kettering cancer center ( mskcc ) and heng criteria .
, college station , tx ) . a p - value of < 0.5 was considered statistically significant . following approval by the institutional review board ( irb ) of the research institute and hospital national cancer center ( irb no .
ncc2015 - 0212 ) , patient record / information was anonymized and de - identified prior to analysis .
all study protocols were conducted according to the ethical guidelines of the world medical association declaration of helsinki - ethical principles for medical research involving human subjects .
data from 262 patients with mrcc treated with systemic agents between 2003 and 2013 were evaluated retrospectively .
patients who were administered it as a systemic therapy between 2003 and 2013 were selected from the prospectively recorded rcc database of the national cancer center hospital , and those administered tt who were treated between 2006 and 2013 were selected .
of the 262 patients , 135 ( 51.5% ) underwent first - line it regimens based on mono or combinational therapy with ifn- , il-2 , 5-fu , or vinblastine . the remaining 127 patients ( 48.5% ) underwent first - line systemic tt .
patients with no follow - up history and who had incomplete rcc treatment histories were excluded .
additional information about the clinical outcomes of 96 patients treated with either tt or it as a sequential second - line systemic therapy was also evaluated .
the choice of it or tt was at the discretion of the treating urologist ( j.c . ) and was based on the patient s histopathology and coverage by the national health insurance system .
combination it comprised different combinations of subcutaneous recombinant human il-2 ( aldesleukin , proleukin , chiron corporation , emeryville , ca ) or recombinant human ifn- ( ifn - alpha-2a , roferon - a , hoffmann - la roche , nutley , nj ) , and intravenous 5-fu ( jw pharm , seoul , korea ) or vinblastine ( united pharm , seoul , korea ) .
the triple or quadruple regimens were administered as follows : il-2 , 20 miu / m on days 35 of weeks 1 and 4 , and 5
miu / m il-2 on days 1 , 3 , and 5 of weeks 2 and 3 ; ifn- , 6
miu / m on day 1 of weeks 1 and 4 and on days 1 , 3 , and 5 of weeks 2 and 3 , and 9
miu / m on days 1 , 3 , and 5 of weeks 5 - 8 ; 5-fu , 750
mg / m once weekly during weeks 5 - 8 ; with ( quadruple ) or without vinblastine ( triple ) at 0.1 mg / kg once weekly during weeks 5 - 8 .
the dual combination regimen of vinblastine plus ifn- was administered as ifn- at 9 miu / m on days 1 , 3 , and 5 each week , and vinblastine at 0.1 mg / kg every 3 weeks .
all tt was administered orally . for sunitinib , each cycle consisted of 50 mg / day for 4 weeks followed by a 2-week hiatus . for sorafenib , each cycle consisted of consecutive 400 mg twice daily per week . for pazopanib , each cycle consisted of consecutive 800 mg once daily per week .
subjects were administered consecutive 10 mg of everolimus once a day per week and 5 mg of axitinib twice a day per week as the second - line tt .
the treatment response was assessed every 4 - 6 weeks for sorafenib , pazopanib , everolimus , and axitinib .
during follow - up , meticulous history taking , physical examination , routine blood tests , abdominal computed tomography ( ct ) , radionuclide bone scan , simple chest radiography , and/or chest ct , and electrocardiography were performed at regular intervals .
in addition , mandatory thyroid function tests and echocardiography were performed in patients scheduled to receive tt .
all responses were evaluated on ct imaging according to the response evaluation criteria in solid tumor ( recist ) ver .
therapeutic responses were assessed at the end of each cycle ( at 8 weeks for the triple and quadruple it regimens ) or every 3 - 4 cycles ( at 9 - 12 weeks for the dual it regimen ) . for tt ,
response was assessed at the end of two cycles and treatment was continued until disease progression .
time to progression and death were assessed using kaplan - meier analysis with the log - rank test .
the orr , pfs , and os of the first- and second - line therapies were assessed according to the systemic agent and the clinical outcomes of sequential treatment with it and tt , and their prognostic stratifications , were also evaluated according to the memorial sloan kettering cancer center ( mskcc ) and heng criteria .
statistical analyses were performed using stata software ( release 9.2 , statacorp . , college station , tx ) .
following approval by the institutional review board ( irb ) of the research institute and hospital national cancer center ( irb no .
ncc2015 - 0212 ) , patient record / information was anonymized and de - identified prior to analysis .
all study protocols were conducted according to the ethical guidelines of the world medical association declaration of helsinki - ethical principles for medical research involving human subjects .
during the treatment period ( median duration , 4.3 months ) and the 24-month follow - up period , the first - line orr , pfs , and os were 41.9% , 8.1 months , and 16.8 months , respectively ( table 1 ) . during these same periods ,
the second - line orr , pfs , and os were 27.5% , 6.5 months , and 15.3 months , respectively .
significantly better prognostic outcomes of second - line pfs were observed in the tt group ( 7.1 months ) compared with the it group ( 2.1 months ) ( p=0.002 ) .
however , second - line os was not significantly different between the tt ( 16.6 months ) and it ( 8.6 months ) groups ( p=0.636 ) . in subgroup analyses of first - line systemic therapies ,
the tt , it , and sequential groups had a pfs of 9.3 , 6.4 , and 5.7 months ( p=0.819 ) , respectively , and an os of 15.8 , 16.5 , and 40.6 months ( p=0.014 ) , respectively ( table 2 , fig .
1 ) . pazopanib provided the best median pfs response , followed by sorafenib , sunitinib , and it ( p=0.053 ) ( table 2 , fig .
the quadruple it regimen had superior pfs to that of it mono , dual , or triple regimens ( p=0.522 ) ( table 2 ) . among the 14 it - treated patients who achieved a complete response ( cr ) , eight ( 5.9% ) remained alive with a mean response duration of 104.542.8 months ( median , 123 months ; range , 33.1 to 156.7 months ) ; four of these ( 3.15% ) also received tt treatment .
for the seven tt - treated patients who achieved a cr , four remained alive , with a median response duration of 22.8 months ( range , 13.9 to 54.8 months ) ( table 2 ) .
for the risk - stratified subgroup analyses that were dependent on the mskcc and heng criteria ( table 3 ) , the clinical outcomes of pfs for each stratified prognostic group were followed subsequently in order according to their consecutive risk groups . when stratified according to the mskcc or heng criteria , treatments had differential outcomes for median os . for the favorable mskcc risk group in the first - line therapy ,
tt showed a superior os compared with it or sequential it plus tt ( p < 0.001 ) ( table 3 ) .
in contrast , for the favorable heng risk group , it had superior os compared with tt or it plus tt ( p < 0.001 ) .
other prognostic outcomes of first - line therapies and pfs and os of second - line therapies , as calculated using the mskcc and heng risk group models , are summarized in table 3 .
since the introduction of tt , the therapeutic regimen paradigm has shifted from it to tt in mrcc .
the prognoses have also improved dramatically in the clinical setting . in the current study ,
differences in prognoses in mrcc patients treated either with it , tt , or sequential therapy as the first- and second - line systemic therapies were examined at a single center during 10 years .
the current study showed that the median pfs and os of it regimens was superior or equivocal to those observed in other western studies on it , and their orr of 41.9% and disease control rate of 69.5% ( 31.1% and 54.8% ; including 59 follow - up loss and death patients ) were superior to those reported in a previous korean study on it ( 18% and 51% , respectively ) ( table 1 ) .
the use of 5-fu or vinblastine chemotherapy in conjunction with it increased the pfs by 0.5 - 3 months in 40.0% of the patients undergoing it treatment , and quadruple it resulted in the best pfs ( 8.8 months ) compared with all other it combinations ( 5.8 - 6.2 months ) ( table 2 ) .
this suggests that the clinical benefit of an it with the addition of a chemotherapy regimen should be carefully considered in terms of whether the increased survival gains would outweigh the likely increase in adverse events .
patients previously treated with high - dose il-2 achieved a 15% of orr with a median duration of 54 months , suggesting that high - dose il-2 treatment may have been curative in a small minority of patients .
there are no clear guidelines regarding patient selection ; however , retrospective studies have suggested that il-2 was more efficacious in patients with a clear cell histology and favorable prognosis .
ifn- , another systemic immunotherapeutic agent for mrcc , has consistently demonstrated low but reproducible responses ( 10%-20% ) with occasional durable responses with a pfs and os of 5 - 5.6 and 4.1 - 21.8 months , respectively .
this is similar to the data of the patients in the current study undergoing ifn- monotherapy who had similar pfs and os ( 5.8 months ) ( table 2 ) and 19.3 months ( 19.3 months , data not shown ) .
a combination of il-2 and ifn- showed a better clinical outcome in terms of orr and pfs when compared with il-2 monotherapy ( table 2 ) .
in addition , sequential therapy with the combined it and tt regimen resulted in a better os ( 40.6 months ) compared to single tt ( 15.8 months ) and single it ( 16.5 months ) treatment regimens ( p=0.014 ) ( table 2 ) .
however , this outstanding sequential therapy os may have resulted from our selection of patients who were capable of surviving it prior to tt and were expected to have a good performance based on favorable prognostic modeling with a fairly low tumor burden and a history of nephrectomy . in particular , patients with rapid progression might be excluded from participation before beginning tt .
therefore , conditional survival may be an important methodology when evaluating the prognosis of mrcc patients treated with sub - sequential tt . in recent decades ,
compared with it , multiple single tts have shown greater activity in terms of pfs , specifically when compared with ifn- .
however , a clinically relevant increase in cr and os has not been reported and the role of tt in increasing the curability of mrcc has not been fully elucidated . from a pharmacological viewpoint , the unsatisfactory results of tt to induce a cr may be explained in part by their mechanism of action , which appears to be more cytostatic than cytotoxic .
the current study also showed that the os ( 15.8 months ) , orr ( 33.9% ) , and cr ( 5.6% ) of tt were either similar or inferior to the os ( 16.5 months ) , orr ( 31.1% ) , and cr ( 10.4% ) of it ( table 2 ) .
the percentage of patients reaching cr for sunitinib , sorafenib , and pazopanib as first - line tt was reported as 1%-3% in earlier real - world clinical trials , post - marketing all - patient surveillance trials , and pivotal trials [ 16 - 18 ]
. the higher cr rate ( 5.6% ) in this study would actually be much lower than observed because patients who stopped therapy after achieving cr during a substantial follow - up had a higher rate of relapse than patients who continued sequential therapy , as shown in a recent , large , retrospective study evaluating mrcc patients who were in cr during tyrosine kinase inhibitor treatment ( either alone or in combination with local treatment ) .
another possible explanation for achievement of high cr would be that it is often integrated with tt with surgery , radiotherapy , or both .
reported a similarly increased cr rate in comparison with the current study in patients treated with tyrosine kinase inhibitors plus surgery ( 4.5% ) when compared to those treated with medical therapy alone ( 1.8% ) .
the current study also showed a significantly longer pfs ( 11.2 months ) and greater cr rates ( 5.4% ) in patients who underwent nephrectomy plus tt compared to patients who underwent tt alone ( pfs , 5.6 months ; cr rate , 1.0% ; data not shown in tables ) .
previous extended - access and post - marketing all - patient surveillance trials have reported 16 - 22%/25.9%/39% of orrs and 5.2 - 9.4/6.0/13.7 months of pfss for sunitinib , sorafenib , and pazopanib in mrcc patients , respectively [ 16 - 18,21 ] .
the orrs for sunitinib , sorafenib , and pazopanib reported in the current study were superior to those reported in previous studies ( 44.1% , 27.3% , and 62.5% , respectively ; data not shown ) ; except for the pfs inferior or similar to previous studies ( 8.5 , 9.0 , and 11.0 months , respectively ) [ 16 - 18,21 ]
. additional evaluation of second - line systemic therapies for their orr , pfs , and os ( 27.5% , 6.5 months , and 15.3 months , respectively ) was similar or superior to that of previous trials with second - line therapy in cytokine- or tt - refractory mrcc patients ( orr , 9% to 23% ; pfs , 4 to 7.4 months ; os , 11.5 to 16.3 months ) .
these differences of orr , pfs , and os are likely due to follow - up time , differences in clinical policies between clinicians surrounding various treatment modalities , differences in baseline study populations such as disease burden , nephrectomy rate , and physical body composition , as has been previously demonstrated for other malignancies .
regarding the analyses of prognostic models , patients with favorable mskcc or heng risk group showed longer survival . in agreement , in the current study , those with favorable mskcc or heng risk group of first- and second - line therapy had a significantly better prognosis compared to those with poor or intermediate risk group ( table 3 ) .
when stratified according to mskcc and heng criteria , the pfs for all groups in the first - line therapy was better in those treated with tt compared to those treated with it .
however , those with a favorable heng risk group treated with it showed a superior os in the first - line therapy , compared to all other groups and treatments .
it was a retrospective study with a small patient population , with a possible patient selection bias based on the era of when systemic therapy was initiated .
the relevance of the stratified findings based on mskcc and heng criteria is not fully understood and should be developed further in future large - scale multicenter studies with a more diverse patient population .
although the orr of tt and it were comparable in this study , tt demonstrated superior pfs and os compared with it in patients with mrcc .
this supports the hypothesis that the clinical outcomes of patients with mrcc have shown significant improvement since the introduction of tt .
 purposethe purpose of this study is to compare the outcomes of first - line systemic targeted therapy ( tt ) and immunotherapy ( it ) in patients with metastatic renal cell carcinoma ( mrcc).materials and methodsthis study was a retrospective review of the data of 262 patients treated with systemic it or tt with tyrosine kinase inhibitors between 2003 and 2013 . 
 the objective response rate ( orr ) , progression - free survival ( pfs ) , and overall survival ( os ) were assessed using response evaluation criteria in solid tumor ver . 
 1.0 criteria and the kaplan - meier method with log - rank test.resultsduring the median 4.3-month treatment and the 24-month follow - up period , the orr / pfs / os of the overall first - line and second - line therapy were 41.9%/8.1 months/16.8 months and 27.5%/6.5 months/15.3 months , respectively . the first - line tt / it / sequential it had a pfs of 9.3/6.4/5.7 months and an os of 15.8/16.5/40.6 months ( all p < 0.05 ) . 
 the second - line of tt / it had a pfs of 7.1/2.1 months ( both p < 0.05 ) and an os of 16.6/8.6 months ( p=0.636 ) , respectively . 
 pazopanib provided the best median pfs of 11.0 months ( p < 0.001 ) and a quadruple it regimen had a superior pfs ( p=0.522 ) . for os , sequential treatment with it and tt was superior compared to treatment with either it or tt alone ( 40.6/16.5/15.8 months , p=0.014 ) . 
 the prognosis according to the memorial sloan kettering cancer center model showed that favorable / intermediate / poor risk groups had a pfs of 8.5/10.4/2.3 months , and an os of 43.1/20.4/5.6 months , respectively . 
 the prognosis calculated using the heng model showed that the favorable / intermediate / poor risk groups had a pfs of 9.2/3.9/2.7 months , and an os of 32.4/16.5/6.1months , respectively ( all p < 0.001).conclusionin patients with mrcc , tt provided a better pfs and os compared with it . 
Introduction
Materials and Methods
1. Patients
2. Treatment regimens
3. Targeted therapy
4. Follow-up
5. Statistical analyses
6. Ethical statements
Results
Discussion
Conclusion