the frequency of upper urinary tract urothelial carcinoma ( utuc ) is approximately 5% of urothelial malignancies and < 10% of renal tumors . this cancer can be treated by radical nephroureterectomy with excision of the bladder cuff , but treatment is often problematic owing to difficulties in early diagnosis , the high incidence of tumor recurrence , and poor prognostic outcomes . because systemic recurrences are common in this disease , it is reasonable to consider perioperative treatments that might reduce this risk . however , few studies have explored such perioperative treatments , including chemotherapy or radiation therapy , and these limited studies have yielded conflicting results . some potential perioperative agents that might confer chemoprotective effects are vitamin a , vitamin e , vitamin c , selenium , nonsteroidal anti - inflammatory drugs , isoflavone , and statins ( hydroxymethylglutaryl - coa - reductase inhibitors ) . of these , statins have been used to treat high cholesterol in general owing to their efficacy and minimal side effects . statins improve the blood lipid profile , treat a number of cardiovascular diseases , and specifically reduce mortality from coronary heart disease . although vascular secondary end points are the main clinical target of these agents , statins also affect other conditions . in particular , a growing body of evidence suggests that statins provide a chemoprotective advantage against many cancers , likely by arresting cell cycle progression , suppressing angiogenesis , inducing apoptosis , and inhibiting tumor growth and metastasis . currently , preclinical data show that statins induce cell cycle arrest and apoptosis and inhibit proliferation in human urothelial carcinoma cell lines . however , the impact of statin use has been investigated mainly in patients with lower urinary tract carcinomas owing to the infrequency of utuc . in previous studies , statin use showed conflicting effects on the prognosis of patients with lower utuc , and only one multi - institutional study did not suggest an influence of statin therapy on utuc prognosis . however , these studies were limited by heterogeneous groups of patients and variable follow - up schedules according to each institution . therefore , we assessed the impact of statins on oncologic outcomes in patients with utuc after radical nephroureterectomy performed at a single center . a review of the medical records of our single institute identified 291 patients with primary utuc who underwent radical nephroureterectomy between january 2006 and december 2011 . patients who had previous or synchronous invasive bladder cancer , who had distant metastasis at diagnosis , or who had received neoadjuvant therapy were excluded . three patients with concomitant invasive bladder cancer and 11 patients with distant metastasis at diagnosis were excluded from analysis . each patient underwent a preoperative evaluation , which included blood tests , urine cytology , cystoscopy , chest x - ray , abdominopelvic computerized tomography , and a bone scan . information regarding medication use ( statin use ) , the presence of comorbid illnesses , smoking history , and alcohol intake history was obtained from the electronic database . because of the retrospective nature of data collection , we were unable to obtain the duration of statin use because this information was not available in the charts . the anesthesiologists used the american society of anesthesiologists score prior to surgery to assess the ability of patients to undergo surgery . in all cases , radical nephroureterectomy with bladder cuff excision was performed and lymphadenectomy was performed when enlarged lymph nodes were either identified on preoperative computed tomography or were palpable during surgery . tumors were pathologically staged by using the 2010 american joint committee on cancer tnm staging system , and tumors were graded according to the 2004 world health organization classification . lymphovascular invasion was defined as the presence of tumor cells within an endothelium - lined space without underlying muscular walls . adjuvant therapy was selectively recommended for patients with locally advanced or node - positive disease on pathology , except for those who could not tolerate chemotherapy of refused treatment . adjuvant therapy was administered to 42 patients ( 12.3% ) , including 31 who received adjuvant chemotherapy and 27 who received adjuvant radiation therapy . follow - up consisted of chest radiography and abdominopelvic computed tomography every 6 months for the first 2 years and annually thereafter . surveillance cystoscopy was generally performed every 3 months for the first 2 years after radical nephroureterectomy , every 6 months for the next 2 years , and annually thereafter . tumor recurrence was defined as local failure in the tumor bed or regional lymph nodes or distant metastasis . since bladder recurrence did not affect survival in the current patient population , this factor was not considered when calculating the rfs rate . the cause of death was determined by chart review and was corroborated by death certificates . the statin user and nonuser subgroups were compared in terms of clinicopathological factors by using pearson chisquare test or fisher exact test for categorical variables and student t - test or mann whitney u - test for continuous variables . kaplan - meier survival curves were used to estimate rfs and css and were compared by using the log - rank test . a cox proportional hazards regression model was used to estimate the prognostic significance of each variable . correlations between outcomes and variables were expressed as hazard ratios ( hrs ) with 95% confidence intervals ( cis ) . all statistical analyses were performed by using the ibm spss statistics ver . 21.0 ( ibm co. , armonk , ny , usa ) . a review of the medical records of our single institute identified 291 patients with primary utuc who underwent radical nephroureterectomy between january 2006 and december 2011 . patients who had previous or synchronous invasive bladder cancer , who had distant metastasis at diagnosis , or who had received neoadjuvant therapy were excluded . three patients with concomitant invasive bladder cancer and 11 patients with distant metastasis at diagnosis were excluded from analysis . each patient underwent a preoperative evaluation , which included blood tests , urine cytology , cystoscopy , chest x - ray , abdominopelvic computerized tomography , and a bone scan . information regarding medication use ( statin use ) , the presence of comorbid illnesses , smoking history , and alcohol intake history was obtained from the electronic database . because of the retrospective nature of data collection , we were unable to obtain the duration of statin use because this information was not available in the charts . the anesthesiologists used the american society of anesthesiologists score prior to surgery to assess the ability of patients to undergo surgery . in all cases , surgery was performed with curative intent . radical nephroureterectomy with bladder cuff excision was performed and lymphadenectomy was performed when enlarged lymph nodes were either identified on preoperative computed tomography or were palpable during surgery . tumors were pathologically staged by using the 2010 american joint committee on cancer tnm staging system , and tumors were graded according to the 2004 world health organization classification . lymphovascular invasion was defined as the presence of tumor cells within an endothelium - lined space without underlying muscular walls . adjuvant therapy was selectively recommended for patients with locally advanced or node - positive disease on pathology , except for those who could not tolerate chemotherapy of refused treatment . adjuvant therapy was administered to 42 patients ( 12.3% ) , including 31 who received adjuvant chemotherapy and 27 who received adjuvant radiation therapy . follow - up consisted of chest radiography and abdominopelvic computed tomography every 6 months for the first 2 years and annually thereafter . surveillance cystoscopy was generally performed every 3 months for the first 2 years after radical nephroureterectomy , every 6 months for the next 2 years , and annually thereafter . tumor recurrence was defined as local failure in the tumor bed or regional lymph nodes or distant metastasis . since bladder recurrence did not affect survival in the current patient population , this factor was not considered when calculating the rfs rate . the cause of death was determined by chart review and was corroborated by death certificates . the statin user and nonuser subgroups were compared in terms of clinicopathological factors by using pearson chisquare test or fisher exact test for categorical variables and student t - test or mann whitney u - test for continuous variables . kaplan - meier survival curves were used to estimate rfs and css and were compared by using the log - rank test . a cox proportional hazards regression model was used to estimate the prognostic significance of each variable . correlations between outcomes and variables were expressed as hazard ratios ( hrs ) with 95% confidence intervals ( cis ) . of the 277 patients , 62 ( 22.4% ) reported being on statins at the time of radical nephroureterectomy , whereas 215 were not . the statins used were lipophilic ( n=57 , 91.9% ) and hydrophilic ( n=5 , 8.1% ) . the two groups differed significantly in terms of age , body mass index ( bmi ) , cardiovascular disease , and diabetes status . compared to the statin nonusers , the statin users were older ( 66.88.8 years vs. 62.710.4 years , p=0.006 ) , had higher bmis ( 25.63.7 kg / m vs. 24.53.2 kg / m , p=0.015 ) , and had higher rates of cardiovascular disease ( 27.4% vs. 15.3% , p=0.039 ) and diabetes ( 32.3% vs. 14.9% , p=0.003 ) . there were no significant differences in tumor stage , grade , lymphovascular disease , surgical margin status , or adjuvant therapy rate between the two groups . at a median follow - up time of 40 months , 58 patients ( 18.8% ) had disease recurrence and 42 patients ( 15.2% ) had already died from utuc progression . of the patients who had died , 7 ( 11.3% ) were statin users and 35 ( 16.3% ) were statin nonusers . the 5-year rfs rates of statin users and nonusers were 78.5% and 72.5% , respectively ( p=0.528 ) ( fig . 1a ) , and the 5-year css rates were 85.6% and 77.7% , respectively ( p=0.516 ) ( fig . the 5-year os rates were 74.5% and 71.4% , respectively ( p=0.945 ) ( fig . , rosuvastatin was excluded ) also had no significant effect on outcomes ( data not shown ) . table 2 presents the results of the univariate and multivariate analyses of rfs and css . multivariate analysis revealed that the only statistically significant predictors of rfs and css were tumor grade , tumor stage , and adjuvant therapy . however , statin use ( hr , 0.47 ; 95% ci , 0.22 - 1.02 ; p=0.056 ) was not an independent prognostic factor for rfs ( hr , 0.47 ; 95% ci , 0.22 - 1.02 ; p=0.056 ) and css ( hr , 0.46 ; 95% ci , 0.18 - 1.14 ; p=0.093 ) . in the multivariate analysis of prognostic factors for os ( data not shown ) , age ( hr , 1.05 ; 95% ci , 1.02 - 1.07 ; p<0.001 ) , tumor grade ( hr , 1.97 ; 95% ci , 1.21 - 3.23 ; p=0.008 ) , tumor stage ( hr , 2.03 ; 95% ci , 1.20 - 3.42 ; p=0.001 ) , surgical margin ( hr , 2.12 ; 95% ci , 1.16 - 3.86 ; p=0.014 ) , and lymph node status ( hr , 2.39 ; 95% ci , 1.34 - 4.26 ; p=0.003 ) were independent prognostic factors for os in patients who underwent radical nephroureterectomy for utuc . of the 277 patients , 62 ( 22.4% ) reported being on statins at the time of radical nephroureterectomy , whereas 215 were not . the statins used were lipophilic ( n=57 , 91.9% ) and hydrophilic ( n=5 , 8.1% ) . the two groups differed significantly in terms of age , body mass index ( bmi ) , cardiovascular disease , and diabetes status . compared to the statin nonusers , the statin users were older ( 66.88.8 years vs. 62.710.4 years , p=0.006 ) , had higher bmis ( 25.63.7 kg / m vs. 24.53.2 kg / m , p=0.015 ) , and had higher rates of cardiovascular disease ( 27.4% vs. 15.3% , p=0.039 ) and diabetes ( 32.3% vs. 14.9% , p=0.003 ) . there were no significant differences in tumor stage , grade , lymphovascular disease , surgical margin status , or adjuvant therapy rate between the two groups . at a median follow - up time of 40 months , 58 patients ( 18.8% ) had disease recurrence and 42 patients ( 15.2% ) had already died from utuc progression . of the patients who had died , 7 ( 11.3% ) the 5-year rfs rates of statin users and nonusers were 78.5% and 72.5% , respectively ( p=0.528 ) ( fig . 1a ) , and the 5-year css rates were 85.6% and 77.7% , respectively ( p=0.516 ) ( fig . the 5-year os rates were 74.5% and 71.4% , respectively ( p=0.945 ) ( fig . , rosuvastatin was excluded ) also had no significant effect on outcomes ( data not shown ) . table 2 presents the results of the univariate and multivariate analyses of rfs and css . multivariate analysis revealed that the only statistically significant predictors of rfs and css were tumor grade , tumor stage , and adjuvant therapy . however , statin use ( hr , 0.47 ; 95% ci , 0.22 - 1.02 ; p=0.056 ) was not an independent prognostic factor for rfs ( hr , 0.47 ; 95% ci , 0.22 - 1.02 ; p=0.056 ) and css ( hr , 0.46 ; 95% ci , 0.18 - 1.14 ; p=0.093 ) . in the multivariate analysis of prognostic factors for os ( data not shown ) , age ( hr , 1.05 ; 95% ci , 1.02 - 1.07 ; p<0.001 ) , tumor grade ( hr , 1.97 ; 95% ci , 1.21 - 3.23 ; p=0.008 ) , tumor stage ( hr , 2.03 ; 95% ci , 1.20 - 3.42 ; p=0.001 ) , surgical margin ( hr , 2.12 ; 95% ci , 1.16 - 3.86 ; p=0.014 ) , and lymph node status ( hr , 2.39 ; 95% ci , 1.34 - 4.26 ; p=0.003 ) were independent prognostic factors for os in patients who underwent radical nephroureterectomy for utuc . currently , statins are being researched in a number of studies for their ability to prevent a variety of cancers , but the results have been inconsistent . one recent study showed that cancer patients who used statins prior to diagnosis had reduced css compared with that of patients who had never taken statins . however , that study did not report on utuc patients specifically and the effects of statin use on the clinical treatment outcomes of urothelial cell carcinoma are unknown . especially in urology , the effect of statins on prostate cancer incidence and disease progression has been investigated in many studies . recent meta - analysis showed a 33% risk reduction for advanced high - grade or metastatic prostate cancer   and that statin use protects against prostate cancer with poorer pathological characteristics . in our previous study , we showed that postoperative statin use decreased the risk of biochemical recurrence , especially in patients with high - risk disease . however , only few studies have investigated the effect of statins on urothelial carcinoma incidence and prognosis . in one previous study that examined the effects of atorvastatin on human bladder cancer cell lines , a significant antiproliferative effect was observed in the statin group compared with controls . in another study using mouse cells transfected with the h - ras oncogene from human bladder carcinoma , the researchers observed that statin treatment significantly inhibited ras oncogene - transformed cells . , only a few studies have focused their investigations on the clinical effect of statins on urothelial carcinoma incidence and prognosis , and these studies have primarily concentrated on bladder carcinoma , not utuc . tsai et al .   suggested that statins may improve local control in patients who underwent concurrent chemoradiotherapy for muscle - invasive bladder cancer . however , this study showed that statin use was associated with local control only in univariate , not multivariate , analysis . recently , one multi - institutional study found that statin use was not associated with rfs or css in patients treated with radical nephroureterectomy for utuc . similarly , statin use was also not associated with rfs or css in patients treated with radical cystectomy for bladder cancer , and statins did not affect the oncologic outcome for non - muscle - invasive bladder cancer . additionally , a recent meta - analysis study showed no significant association between statin use and the risk of bladder cancer . furthermore , there have been 5 retrospective studies exploring the impact of statin use on patient responses to bacillus calmette - guerin ( bcg ) immunotherapy . reported that concurrent statin therapy with bcg might reduce the clinical efficacy of bcg therapy . statin users were more likely to proceed to more aggressive disease as well as to require radical cystectomy . however , subsequent studies failed to confirm that statin therapy affects patient responses to bcg . these studies found no differences between statin users and nonusers in the mean number of recurrences or incidence of disease progression , css , or os . overall , these results are consistent with the findings in our study , in which statin use did not improve rfs , css , or os after radical nephroureterectomy for utuc . first , because the findings represent the clinical experience of a single center , the rate of patients taking statins was lower than in a previous study . however , the prevalence of statin use in patients 50 years or older was 22.8% in 2008 . second , medical chart review can be an unreliable method for determining the duration and dosage of medications used by a study population , because much of this information may not be reported consistently in the medical records . it would be interesting to assess the correlation between the dosage and the duration of statin use with prognosis , but unfortunately , this information was not available in the patient records . therefore , well - designed , prospective , randomized trials that include a large patient population are warranted . despite the limitations of the present study , to the best of our knowledge , this is the first single - center study to investigate the potential impact of statin use on the clinical outcomes of patients with utuc being treated with radical nephroureterectomy . in patients undergoing radical nephroureterectomy for utuc , statin use was not associated with rfs , css , or os . owing to the inherent limitations of this retrospective study , the potential antineoplastic effect of statins needs further investigation prospectively .
purposethe objective was to investigate the impact of statin use on prognosis after radical nephroureterectomy for upper urinary tract urothelial carcinoma ( utuc).materials and methodsa retrospective review of medical records identified 277 patients who underwent radical nephroureterectomy for primary utuc at asan medical center between january 2006 and december 2011 . 
 information on preoperative statin use was obtained from patient charts in an electronic database . 
 we assessed the impact of statin use on recurrence - free survival ( rfs ) , cancer - specific survival ( css ) , and overall survival ( os).resultsof these 277 patients , 62 ( 22.4% ) were taking statin medications . compared to the statin nonusers , the statin users were older , had a higher body mass index , and had higher rates of cardiovascular disease and diabetes . 
 the 5-year rfs rates of statin users and nonusers were 78.5% and 72.5% , respectively ( p=0.528 ) ; the 5-year css rates were 85.6% and 77.7% , respectively ( p=0.516 ) ; and the 5-year os rates were 74.5% and 71.4% , respectively ( p=0.945 ) . in the multivariate analysis , statin use was not an independent prognostic factor for rfs ( hazard ratio , 0.47 ; p=0.056 ) , css ( hazard ratio , 0.46 ; p=0.093 ) , or os ( hazard ratio , 0.59 ; p=0.144 ) in patients who underwent radical nephroureterectomy for utuc.conclusionsstatin use was not associated with improved rfs , css , or os in the sample population of patients with utuc .