although surgery is curative for localized disease , up to 30% of patients with rcc present with metastatic disease at the time of diagnosis , and more than 25% of patients with locally advanced rcc develop distant metastasis despite curative resection . since rcc is highly resistant to chemotherapy , high dose interleukin-2 or interferon - alfa therapy is widely used as a first - line treatment of metastatic disease , but they provide only a modest response rate of less than 20% . thus , the outcome of metastatic rcc is quietly depressing : the 5-year overall survival rate is less than 10% . effective systemic therapy for rcc is mandatory . in conventional rcc , the loss of von hippel - lindau protein function leads to overexpression of vascular endothelial growth factor ( vegf ) and platelet - derived growth factor that promote tumor angiogenesis . sunitinib is an orally active multi - targeted tyrosine kinase inhibitor that specifically inhibits vegf receptor ( vegfr ) , platelet - derived growth factor receptor ( pdgfr ) , fms - like tyrosine kinase-3 ( flt-3 ) , and stem c - kit protein ( c - kit ) . the efficacy on metastatic rcc has been confirmed in both phase ii and iii trials , where it was shown to improve the median progression - free survival ( pfs ) , yield a higher response rate ( rr ) , and afford a better quality of life over interferon - alfa [ 9 - 11 ] . based on current data , sunitinib is now the preferred drug for first - line treatment of metastatic rcc . although the nature of these variations and associated molecular basis is not demonstrated , it is reasonable to evaluate the efficacy of sunitinib on metastatic rcc in those of different ethnic backgrounds . therefore , we perfomed this retrospective study to assess the efficacy and safety of sunitinib in korean patients with metastatic rcc using an institutional treatment protocol . the medical records of patients treated with sunitinib for metastatic rcc were retrospectively reviewed between september 2007 and december 2009 . the inclusion criteria were as follows : histologically confirmed clear - cell rcc ; metastases measurable on computed tomography ( ct ) or magnetic resonance imaging ( mri ) ; a performance status of 0 - 2 based on eastern cooperative oncology group ( ecog ) criteria . patient demographics , prior therapy , best responses , and relevant toxicities were obtained from medical records , and survival data were collected by telephone interviews . risk factors associated with shorter survival were assessed according to the memorial sloan - kettering cancer center ( mskcc ) risk classification : a low serum hemoglobin level , an elevated corrected serum calcium level , an elevated serum lactate dehydrogenase level , a poor performance status , and an interval of less than 1 year between diagnosis and treatment . sunitinib was administered orally at a dose of 50 mg daily , consisting of 4 weeks of treatment followed by a 2-week rest period in cycles of 6 weeks ( schedule 4 - 2 ) . dose reduction of sunitinib was allowed to 37.5 mg and then 25 mg daily depending on the type and severity of adverse events . treatment with sunitinib was continued until the occurrence of disease progression , unacceptable adverse events , or patient withdrawal . the primary end point of this study was the objective clinical response ( complete response , partial response , stable disease , or progressive disease ) , assessed by response evaluation criteria in solid tumors ( recist ) using regular physical examinations , ct / mri , and bone scans ( if bone metastases were present at baseline ) after each cycle for the first 4 cycles thereafter until the end of treatment . the secondary end points were progression free survival ( pfs ) and overall survival ( os ) rates . pfs was defined as the time from the start of treatment to the date of progressive disease or death . os was defined as the time from start of treatment to death or the date at which patients were last known to be alive . the adverse events secondary to treatment were evaluated at each visit according to the national cancer institute common terminology criteria for adverse events ( ctcae , version 3.0 ) . estimates of median pfs and os were calculated using the kaplan - meier method , and 95% cis were considered statistically significant . the medical records of patients treated with sunitinib for metastatic rcc were retrospectively reviewed between september 2007 and december 2009 . the inclusion criteria were as follows : histologically confirmed clear - cell rcc ; metastases measurable on computed tomography ( ct ) or magnetic resonance imaging ( mri ) ; a performance status of 0 - 2 based on eastern cooperative oncology group ( ecog ) criteria . patient demographics , prior therapy , best responses , and relevant toxicities were obtained from medical records , and survival data were collected by telephone interviews . risk factors associated with shorter survival were assessed according to the memorial sloan - kettering cancer center ( mskcc ) risk classification : a low serum hemoglobin level , an elevated corrected serum calcium level , an elevated serum lactate dehydrogenase level , a poor performance status , and an interval of less than 1 year between diagnosis and treatment . sunitinib was administered orally at a dose of 50 mg daily , consisting of 4 weeks of treatment followed by a 2-week rest period in cycles of 6 weeks ( schedule 4 - 2 ) . dose reduction of sunitinib was allowed to 37.5 mg and then 25 mg daily depending on the type and severity of adverse events . treatment with sunitinib was continued until the occurrence of disease progression , unacceptable adverse events , or patient withdrawal . the primary end point of this study was the objective clinical response ( complete response , partial response , stable disease , or progressive disease ) , assessed by response evaluation criteria in solid tumors ( recist ) using regular physical examinations , ct / mri , and bone scans ( if bone metastases were present at baseline ) after each cycle for the first 4 cycles thereafter until the end of treatment . the secondary end points were progression free survival ( pfs ) and overall survival ( os ) rates . pfs was defined as the time from the start of treatment to the date of progressive disease or death . os was defined as the time from start of treatment to death or the date at which patients were last known to be alive . the adverse events secondary to treatment were evaluated at each visit according to the national cancer institute common terminology criteria for adverse events ( ctcae , version 3.0 ) . estimates of median pfs and os were calculated using the kaplan - meier method , and 95% cis were considered statistically significant . between july 2007 and march 2010 , all twenty - one patients who had metastatic rcc with a clear - cell component were included in the analysis ( table 1 , 2 ) . there were 17 males ( 81% ) and 4 females ( 19% ) , and the median age was 63.9 ( range , 46 - 75 years ) . of those patients , 4 patients ( 19.0% ) had low - risk disease , 10 patients ( 47.6% ) had intermediate - risk disease , and 7 patients ( 33.3% ) had high - risk disease according to the mskcc criteria . the previous treatments were as follows : previous nephrectomy in 13 patients ( 61.9% ) , cytokine therapy in 7 patients ( 33.3% ) , and radiation therapy in 3 patients ( 14.3% ) . the most prevalent sites of metastases were as follows : the lung in 15 patients ( 71.4% ) , lymph nodes in 9 patients ( 42.9% ) , bone in 7 patients ( 33.3% ) , and liver in 3 patients ( 14.3% ) . after a median of 17.4 months ( range , 5.7 - 33.1 months ) of treatment , 14 patients ( 66.7% ) remained alive with the disease , and treatment was ongoing in 11 patients ( 52.4% ) . reasons for discontinuing treatment were progressive disease in 2 patients and adverse events in 1 patient . according to assessment with the recist criteria , 11 patients ( 52.4% ) had an objective response rate , with a complete response in 1 patient ( 4.8% ) , and a partial response in 10 patients ( 47.6% ) as the best tumor response rate ( table 3 ) . the median pfs was 13.4 months ( 95% confidence interval [ ci ] , range , 12.3 - 14.5 months ) ( fig . 1 ) , and the median os was 28.1 months ( 95% ci , 21.8 - 34.4 months ) ( fig . all patients experienced adverse events of some sort : fatigue , diarrhea , and hand - foot syndrome were the most common adverse effects . however , the treatment protocol under study was well tolerated and most patients experienced reversible grade 1 or 2 toxicities ( table 4 ) . the most commonly observed severe adverse events were hand - foot syndrome , fatigue , and generalized edema ; hand - foot syndrome was observed in 4 patients ( 19.0% ) , fatigue was observed in 3 patients ( 14.3% ) , and generalized edema was observed in 3 patients ( 14.3% ) as grade 3 or 4 . the most common laboratory abnormalities of grade 3 or 4 were neutropenia , thrombocytopenia , and anemia , with neutropenia in 6 patients ( 28.6% ) , thrombocytopenia in 6 patients ( 28.6% ) , and anemia in 4 patients ( 19.0% ) . neutropenia was observed in 6 patients ( 28.6% ) , but there was no occurrence of associated fever or sepsis . thrombocytopenia was observed in 6 patients ( 28.6% ) , but there was no clinical significance such as bleeding tendencies . 1 patient ( 4.8% ) experienced hypothyroidism and needed thyroid hormone replacement . a total of 6 patients ( 29% ) required dose reduction from 50 mg / day to 37.5 mg / day with further reductions to 25 mg / day due to grade 3 or 4 adverse events , and 1 patient ( 4.8% ) discontinued treatment due to severe adverse events . the remaining 14 patients ( 66.7% ) tolerated and continued treatment with a standard dose of sunitinib . between july 2007 and march 2010 , all twenty - one patients who had metastatic rcc with a clear - cell component were included in the analysis ( table 1 , 2 ) . there were 17 males ( 81% ) and 4 females ( 19% ) , and the median age was 63.9 ( range , 46 - 75 years ) . of those patients , 4 patients ( 19.0% ) had low - risk disease , 10 patients ( 47.6% ) had intermediate - risk disease , and 7 patients ( 33.3% ) had high - risk disease according to the mskcc criteria . the previous treatments were as follows : previous nephrectomy in 13 patients ( 61.9% ) , cytokine therapy in 7 patients ( 33.3% ) , and radiation therapy in 3 patients ( 14.3% ) . the most prevalent sites of metastases were as follows : the lung in 15 patients ( 71.4% ) , lymph nodes in 9 patients ( 42.9% ) , bone in 7 patients ( 33.3% ) , and liver in 3 patients ( 14.3% ) . after a median of 17.4 months ( range , 5.7 - 33.1 months ) of treatment , 14 patients ( 66.7% ) remained alive with the disease , and treatment was ongoing in 11 patients ( 52.4% ) . reasons for discontinuing treatment were progressive disease in 2 patients and adverse events in 1 patient . according to assessment with the recist criteria , 11 patients ( 52.4% ) had an objective response rate , with a complete response in 1 patient ( 4.8% ) , and a partial response in 10 patients ( 47.6% ) as the best tumor response rate ( table 3 ) . the median pfs was 13.4 months ( 95% confidence interval [ ci ] , range , 12.3 - 14.5 months ) ( fig . 1 ) , and the median os was 28.1 months ( 95% ci , 21.8 - 34.4 months ) ( fig . all patients experienced adverse events of some sort : fatigue , diarrhea , and hand - foot syndrome were the most common adverse effects . however , the treatment protocol under study was well tolerated and most patients experienced reversible grade 1 or 2 toxicities ( table 4 ) . the most commonly observed severe adverse events were hand - foot syndrome , fatigue , and generalized edema ; hand - foot syndrome was observed in 4 patients ( 19.0% ) , fatigue was observed in 3 patients ( 14.3% ) , and generalized edema was observed in 3 patients ( 14.3% ) as grade 3 or 4 . the most common laboratory abnormalities of grade 3 or 4 were neutropenia , thrombocytopenia , and anemia , with neutropenia in 6 patients ( 28.6% ) , thrombocytopenia in 6 patients ( 28.6% ) , and anemia in 4 patients ( 19.0% ) . neutropenia was observed in 6 patients ( 28.6% ) , but there was no occurrence of associated fever or sepsis . thrombocytopenia was observed in 6 patients ( 28.6% ) , but there was no clinical significance such as bleeding tendencies a total of 6 patients ( 29% ) required dose reduction from 50 mg / day to 37.5 mg / day with further reductions to 25 mg / day due to grade 3 or 4 adverse events , and 1 patient ( 4.8% ) discontinued treatment due to severe adverse events . the remaining 14 patients ( 66.7% ) tolerated and continued treatment with a standard dose of sunitinib . rcc is one of the most challenging malignancies with a dismal prognosis because of the modest response to conventional cytotoxic chemotherapeutic agents and limited sensitivity to radiation therapy . cytokine therapy with interferon - alfa or il-2 have been the main treatment options for metastatic disease , but these agents have limited efficacy and are associated with considerable toxic effects . recent advances in understanding the molecular biology of rcc have led to the development of several systemic therapeutic agents targeting the vegf and mammalian target of rapamycin ( mtor ) pathways as first and second line treatments for metastatic disease , with impressive improvements in oncologic outcome . sunitinib is one of several agents , including sorafenib , bevacizumab , and temsirolimus , which target the inhibition of pro - angiogenic growth factor activity and have shown favorable results in clinical trials against metastatic clear - cell rcc [ 15 - 17 ] . recent studies have confirmed the efficacy of sunitinib as a first line treatment for metastatic clear - cell rcc , but these series were mainly performed in different ethnicities in western countries . thus , the potential ethnic differences in the efficacy and safety of sunitinib have not been established . this study evaluated whether korean patients with metastatic rcc had comparable oncologic outcomes and safety as patients in previous randomized studies . in patients with a poor prognosis according to the mskcc criteria , temsirolimus is recommended as a first - line treatment , with sunitinib as a viable alternative , but temsirolimus is not available for korean patients because of problems related to the insurance system ; more patients with poor prognostic factors were included in this study . in terms of he considering the selection bias of randomized controlled trials which include relatively more favorable or intermediate risk group , the results of this study seem to reflect more reliable results in korean clinical practice . for the treatment outcome , sunitinib treatment showed an objective response rate of 39% ( range , 34 - 44% ) and a pfs of 11.0 months ( range , 10.7 - 13.4 months ) as well as an os of 26.4 months ( range , 23.0 - 32.9 months ) in previous phase iii randomized trials . in the current study , the objective response rate was 52.4% , which included a complete response of 4.8% , and a partial response of 47.6% as the best response rates . the median pfs and os were 13.4 months and 28.1 months , respectively . even though it is difficult to directly compare this retrospective study with previous randomized trials , it is obvious that metastatic rcc patients benefitted from sunitinib treatment . all patients experienced treatment - related adverse events , the majority of which were grade 1 or 2 in severity . fatigue , diarrhea , and hand - foot syndrome were the most frequent adverse events , but grade 3 or 4 adverse events were not frequent and were manageable . most of patients were able to resume sunitinib treatment following dose reduction , and only 1 patient among all cases discontinued because of serious adverse events . previous trials have reported that side effects of sunitinib treatment were reversible and tolerable ; patients with grade 3 or 4 side effects did not exceed 10% . nevertheless , routine monitoring such as evaluation of blood pressure / ejection fraction and a thyroid function test is recommended because there is possibility of serious adverse events . emerging safety data indicate that cardiotoxicity may be associated with sunitinib ; left ventricular dysfunction is the main cardiac side effect of sunitinib and might be partly a result of cardiomyocyte toxicity exacerbated by hypertension . therefore , blood pressure and left ventricular ejection fraction should be monitored , especially in patients with cardiac risk factors . it is reported that in patients treated with sunitinib , 85% of patients had abnormal results on thyroid function tests , including elevation of thyroid stimulating hormone levels , decreased t3 levels , and less commonly , decreased t4 or free - thyroxine index levels . because an abnormal thyroid function test may rapidly progress from mild to profound , regular surveillance is warranted at baseline and every 2 - 3 months . in terms of adverse events , neutropenia , thrombocytopenia , and anemia were the most frequent grade 3 or 4 laboratory abnormalities reported previously , and most of them were improved by dose reduction . neutropenia was observed in 6 patients ( 28.6% ) , but there was no event of associated fever or sepsis ; thrombocytopenia was observed in 6 patients ( 28.6% ) , but there was no clinical significance such as bleeding tendencies ; anemia increased amylase / lipase was observed in 7 patients ( 33.3% ) , but there were no associated clinical manifestations of pancreatitis . compared to western trials , sunitinib treatment in korean patients achieved favorable oncological outcomes in terms of objective response rate , pfs , and os . it is interesting to note that the favorable outcomes of the current study are consistent with previous korean studies . although the underlying reason for such a discrepancy remains unclear at this time , one possible explanation is the inherent differences caused by ethnic backgrounds . further large prospective studies are required to clarify whether the ethnic background and its associated molecular mechanisms contribute to the difference in the efficacy of sunitinib across ethnic groups . in terms of adverse effects , a higher incidence of hand - foot syndrome and facial / generalized edema were observed relative to western trials , but they were mainly mild to moderate , and managed readily . this was a retrospective analysis of a small number of patients treated at a single institution , which allows for potential selection bias . furthermore , survival benefit may not be weighted properly because this was not a randomized controlled trial . sunitinib was efficacious and was well tolerated in korean patients ; the objective response rate , pfs , and os in korean patients were compatible with the oncologic outcomes in previous randomized trials . further large prospective investigations are required to clarify such favorable efficacy profiles in korean patients . sunitinib was efficacious in the treatment of metastatic clear - cell rcc , and was well tolerated in korean patients . the objective response rate , pfs , and os in korean patients were compatible with the benefits shown in previous randomized trials . although sunitinib treatment - related adverse events such as hand - foot syndrome and facial / generalized edema were observed in higher incidence than in western trials , they were mainly mild to moderate , and readily managed .