Korean J Urol Oncol 2013;11(3):1-11 한국인전립선암환자에서술전중등도위험군에서술후고위험군으로이행할수있는인자 : 다기관연구 1 전남대학교의과대학비뇨기과학교실, 2 조선대학교의과대학비뇨기과학교실, 3 전북대학교의학전문대학원비뇨기과학교실, 원광대학교의과대학비뇨기과학교실, 광주기독병원비뇨기과 유제국 1 ㆍ황인상 1 ㆍ임동훈 2 ㆍ정영범 3 ㆍ박승철 ㆍ노준화 ㆍ권동득 1 ㆍ강택원 1 Predictors for Migrating to High-Risk Prostate Cancer from Intermediate-Risk Prostate Cancer in Korean Patients: Multicenter Study Je Guk Ryu 1, Insang Hwang 1, Dong Hun Im 2, Young Beom Jeong 3, Seung Chol Park, Joonwha Noh, Dong Deuk Kwon 1, Taek Won Kang 1 Department of Urology, 1 Chonnam National University Medical School, 2 Chosun University Medical School, Gwangju, 3 Chonbuk National University Medical School, Jeonju, Wonkwang University School of Medicine, Iksan, Kwangju Christian Hospital, Gwangju, Korea Purpose: We aimed to examine a change and relevant predictors in intermediate-risk prostate cancer which have a wide range of treatment options from active surveillance to radical prostatectomy (RP). Materials and Methods: Of 1,19 patients who underwent RP in multi-institution between January 2009 and December 2012, 390 patients who were classified as intermediate-risk prostate cancer group by preoperative evaluation according to NCCN guideline were enrolled in this retrospective study. The rates of Gleason score upgrading, upstaging and migrating to high-risk prostate cancer group at final pathology and there risk factors were assessed. Results: The mean age of enrolled patients were.33±.1 years with mean PSA level of 9.3±.3 ng/ml. The number of patients with worsening upgrading, worsening upstaging and worsening prognosis were 2 (10.%), 83 (21.28%) and 108 (2.%), respectively. In analysis compared between upgrading group and non-upgrading group, there was no difference in patient's features. However, in analysis on upstaging and worsening prognosis, serum PSA (p=0.029, p=0.02) and %positive biopsy core (p=0.010, p=0.013) showed significant difference. In univariable analysis, serum PSA (p=0.030, p=0.02) and %positive biopsy core (p=0.00, p=0.01) were predictive of upstaging and worsening prognosis, also, in multivariable analysis, serum PSA (p=0.01) and %positive biopsy core (p=0.02) were statistically relevant factors of worsening upstaging. Conclusions: In this study, 2.% of patients with preoperative intermediate-risk prostate cancer were re-stratified into high-risk prostate cancer group after RP. Serum PSA and %positive biopsy core were the predictive factors for migrating to high risk group. (Korean J Urol Oncol 2013;11:1-11) Key Words: Prostate cancer, Biopsy, Prostatectomy, Gleason score Received November, 2013, Revised December, 2013, Accepted December 12, 2013 Corresponding Author: Taek Won Kang, Department of Urology, Chonnam National University Medical School, 2, Jebong-ro, Dong-gu, Gwangju 01-, Korea. Tel: 82-2-220-03, Fax: 82-2-22-13, E-mail: sydad@hanmail.net This study was supported by a grant (CRI10001-1) of the Chonnam National University Hospital Research Institute of Clinical Medicine. 서론전립선암은 2008년전세계적으로 900,000명이상이새로진단되었고, 이질병으로인해 20,000명이사망하였다. 이는모든암중에서두번째로많이진단되었으며암으로 1
1 대한비뇨기종양학술지 : 제 11 권제 3 호 2013 인한사망원인의여섯번째에해당한다. 1 최근국내에서보고된전립선암의 년상대생존률은 90.2% 로미국의 99.2% 에비해낮고, 특히미국의경우 82% 가국소전립선암으로발견되는데비해우리나라는 % 만이국소암으로진단되어치료된다. 2 이처럼미국이나유럽의경우와우리나라의상황이매우다른시점에서미국이나유럽의치료방침을그대로수용하는것은어려움이있다. 국소전립선암의치료는적극적감시 (active surveillance, AS), 대기요법 (watchful waiting, WW), 근치적전립선절제술 (radical prostatectomy, RP), 방사선치료, 최소침습적치료등으로다양하며, 치료선택은수술전시행하는조직검사상의 Gleason score (GS) 나전립선특이항원 (prostate specific antigen, PSA), 임상적병기에의해결정되는전립선암위험도분류 (prostate cancer risk group) 를참고하는경우가많다. 3 하지만최근발표된여러논문들은수술전평가된 GS 나임상적병기가상당히많은수의환자에서 RP 후시행하는병리학적결과와다르다는것을보고하고있다., 이러한경향은환자치료방침을결정할때반드시고려되어야될사항으로, 이러한변화를예측할수있는임상적, 병리학적인자들에대한연구가현재활발히진행되고있으나논문마다다른결과를보여주고있어아직까지공인된예측인자는없는실정이다. -8 게다가이러한연구들은현재치료방침이 AS와 RP 사이에서논란이되고있는저위험군전립선암에집중되어있다. 치료방침이비교적명확한고위험군전립선암에비하여치료방법이다양하고치료결정시기대수명을고려해야하는중등도위험군환자의경우, 수술후병리학적결과를예측할수있는정보가매우부족하여환자와의사가만족할수있는치료방침을결정하는데어려움이있다. 본연구에서는중등도위험군환자들의수술전과수술후의전립선암위험도분류의차이를분석하고이를예측할수있는인자들을찾고자하였다. 대상및방법 1. Patient selection 2009년 1월부터 2012년 12월까지호남지역 개병원 ( 전남대학교병원, 전북대학교병원, 조선대학교병원, 원광대학교병원, 광주기독병원 ) 에서 RP를시행받은환자 1,19명중수술전평가에서중등도위험군전립선암으로분류된 390명이이후향적연구에포함되었다. 전립선암의위험도평가는 NCCN guideline에따라이루어졌는데, PSA 수치가 10 이상 20 미만이거나, 수술전조직검사상 GS가 이거나, 임상적병기가 T2b 또는 T2c인환자들을대상으로분석을시행하였다. 3 GS 8 이상의고위험군으로분류될수있는환 자는제외하였다. 2. Data collection 대상환자들의임상적, 병리학적특징들을비교, 분석하기위해나이, 키, 몸무게, PSA, 전립선부피, 수술전조직검사상 GS, %positive biopsy core ( 조직검사를시행한총 core 수중전립선암이나온 core 수의백분율 ) 와수술전임상적병기를분석하였다. 전립선부피는경직장초음파를이용하여측정된전립선의부피로적용하였으며수술전임상적병기 (ct stage) 는직상수지검사와전립선 MRI를이용하여평가하였다. 환자의수술후정보로는 RP 후전립선조직검사상의 GS, 병리학적병기 (pt stage), 임파선침윤이나수술경계부위침범 (surgical margin involvement), 전립선암의전립선밖으로의확장 (extraprostatic extension) 여부가포함되었다. 3. Definition of worsening upgrading, worsening upstaging and worsening prognosis 환자들의수술전, 후의임상적, 병리학적특징들을비교하여 worsening upgrading, worsening upstaging 및 worsening prognosis 여부에따라환자들을분류하였다. worsening upgrading 은수술전조직검사상의 GS가 이하였던환자에서수술후조직검사상 GS가 8 이상으로나온것으로하였으며, worsening upstaging 은수술전임상병기가 T2c 이하였던환자가수술후조직검사상병리학적병기가 T3a 이상으로확정된것으로정의하였다. 또이러한전립선암의 GS 및병기의변화에따라수술전중등도위험군으로평가되었던환자들이수술후고위험군환자로재평가된것을 worsening prognosis 로정의하였다.. Statistical analysis 모든통계적인산술은 SPSS (version 20, Chicago, IL) 를사용하였다. 중등도위험군의전립선암환자에서수술의병리적변화에대한인자를분석하기위해서각군간의변화는 Chi-Square test 및 t-test를시행하였고, p값이 0.0 미만인경우를통계학적으로유의한것으로판정하였다. 또한각인자들의영향을분석하기위해서다변수및단변수로지스틱회귀분석을시행하였다. 결과연구에포함된중등도위험군전립선암환자들의수술전기본특이사항은 Table 1에기술되어있다. 환자들의평균나이는.33±.1세였으며평균혈청 PSA는 9.3±.3
유제국외 :Risk of Migration from Intermediate to High Risk after RP 1 ng/ml였다. 중등도위험군전립선암환자중수술후 worsening upgrading, worsening upstaging 및 worsening prognosis 를보인군은각각 2명 (10.%), 83명 (21.28%), 108 명 (2.%) 였다. Worsening upgrading 여부에따라환자들을나누어비교한분석해서수술전환자의인자중통계적으로유의한차이를보이는것은없었지만 RP 후조직검사결과에서전립선암의전립선밖으로의확장이 worsening upgrading 군 Table 1. Patient characteristics Prostate weight (ml) Gleason score sum Worsening upgrading Worsening upstaging Worsening prognosis.33±.1 2.3±2.98 9.3±.3 32.8±1.21 8 (2.0%) 12 (3.1%) 1 (39.%) 21 (.%) 2 (10.%) 83 (21.28%) 108 (2.9%) 에서그렇지않은군보다많은것으로확인되었다 (0.% vs. 1.%, p=0.001) (Table 2). Table 3은 worsening upstaging 여부에따른분석이다. 수술전환자인자중혈청 PSA (p=0.029) 와 %positive biopsy core (p=0.010) 가그렇지않은군에비하여 worsening upstaging 군에서의미있게높게나왔으며수술후조직검사에서도임파선침윤 (.2% vs. 2.3%, p=0.02) 과수술경계부위침범 (12.0% vs..%, p=0.038) 이 worsening upstaging 군에서유의하게많이나왔다. 또한수술전조직검사로확인된 GS는두군에서큰차이가없었으나 (p=0.1), 수술후조직검사에서는의의있는차이가있었다 (p=0.001). Worsening upstaging 을예측하는인자를찾기위한수술전환자인자의단변수및다변수분석에서혈청 PSA (OR 1.03, p=0.030, OR 1.09, p=0.01) 와 %positive biopsy core (OR 1.01, p=0.00, OR 1.012, p=0.02) 가수술후 worsening upstaging 을의미있게증가시켰다 (Table ). 수술후 GS와병기의변화에따라전립선암위험도분류가고위험도군으로바뀐것을 worsening prognosis 로정의하였고이에따라환자들을두군으로나누어시행한분석의결과는 Table 에정리하였다. Worsening upstaging 에서의결과와비슷하게수술전환자인자중혈청 PSA (p=0.02) 와 %positive biopsy core (p=0.013) 가 worsening Table 2. Comparison between worsening upgrading group versus non-upgrading group Worsening upgrading (n=2) Non-upgrading (n=38) p-value Prostate volume (ml) %positive biopsy core (%) Preoperative Gleason score sum.33±. 2.32±2.8 10.0±.8 30.1±1.21 3.39±23.8 0 (0%) 0 (0%) 21 (0.0%) 21 (0.0%).33±.2 2.28±2.99 9.2±.28 32.9±1.9 3.09±22.28 8 (2.3%) 12 (3.%) 133 (38.2%) 19 (.0%) 0.998 0.11 0.2 0.312 0.89 0.09 Postoperative pathology T stage T1c T2a T2b T2c T3a T3b Lymph node invasion Positive surgical margin Extraprostatic extension 0 (0%) (11.9%) 1 (2.%) 19 (.2%) 1 (3.%) 2 (.8%) 2 (.8%) 3 (.1%) 1 (0.%) 2 (0.%) (1.%) (1.%) 220 (3.2%) (1.8%) 11 (3.2%) 11 (3.2%) 2 (.9) 1 (1.%) 0.08 0.8 0.93 0.001
18 대한비뇨기종양학술지 : 제 11 권제 3 호 2013 Table 3. Comparison between worsening upstaging group versus non-upstaging group Worsening upstaging group (n=83) Non-upstaging group (n=30) p-value Prostate volume (ml) %positive biopsy core (%) Preoperative Gleason score sum 8.00±. 2.8±3.23 10.2±.09 31.13±13.2 3.±2. 2 (2.%) 1 (1.2%) 2 (30.1%) (.3%).1±.29 2.2±2.91 9.09±.38 33.11±1.9 3.2±21.1 (2.0%) 11 (3.%) 129 (2.0%) 11 (2.%) 0.2 0.33 0.029 0.302 0.010 0.1 Postoperative pathology Gleason score sum 8 9 Lymph node invasion Positive surgical margin 1 (1.2%) 1 (1.2%) 3 (3.%) 1 (3.%) 8 (9.%) 9 (10.8%) (.2%) 10 (12.0%) 2 (0.%) 28 (9.1%) (21.2%) 18 (0.9%) 19 (.2%) (2.0%) (2.3%) 1 (.%) 0.001 0.02 0.038 Table. Univariable and multivariable analysis for the prediction of post-operative upstaging Univariable analysis Odd ratio 9% CI p-value Age (continuous) 1.023 1.03 1.01 1.9 0.983-1.0 1.00-1.123 1.00-1.02 0.900-2.82 0.2 0.030 0.00 0.120 Multivariable analysis Odd ratio 9% CI p-value 1.09 1.012 1. 1.01-1.19 1.000-1.02 0.89-2. 0.01 0.02 0.129 prognosis 군에서더높게나왔으나수술후조직검사에서임파선침윤 (p=0.130) 과수술경계부위침범 (p=0.11) 은두군에서차이가없었다. Worsening prognosis 를예측하는인자를찾기위한단변수분석에서혈청 PSA (OR 1.03, p=0.030) 와 %positive biopsy core (OR 1.01, p=0.00) 는 worsening prognosis 의위험도를증가시키는것으로보였으며역시다변수분석에서도혈청 PSA (OR 1.09, p=0.01) 와 %positive biopsy core (OR 1.012, p=0.02) 가위험도를높이는인자였다 (Table ). 고찰본연구에서중등도위험군전립선암환자중약 30% 가수술후고위험군으로재평가되었다. Worsening upgrading 를예측할수있는수술전환자인자는없었으나혈청 PSA와 %positive biopsy core는 worsening upstaging 과 worsening prognosis 의위험도를통계적으로유의하게증가시켰다. 또한 worsening upgrading 군에서그렇지않은군보다수술후병기가 T3 이상으로증가하는 worsening
유제국외 :Risk of Migration from Intermediate to High Risk after RP 19 Table. Comparison between worsening prognosis group versus non-worsening prognosis group Worsening prognosis group (n=108) Non-worsening prognosis group (n=282) p-value Prostate weight (ml) %positive biopsy core (%) Preoperative Gleason score sum.83±.9 2.88±3.1 10.0±.3 31.13±1.12 1.8±2.2 2 (1.9) 1 (0.9) 39 (33.3) 9 (3.9).1±.3 2.1±2.89 9.0±.32 32.29±1.23 3.22±21.02 (2.1) 11 (3.9) 118 (1.8) 1 (2.1) 0.320 0.03 0.02 0.21 0.013 0.1 Postoperative pathology Lymph node invasion Positive surgical margin (.) 11 (10.2) (2.) 1 (.) 0.130 0.11 Table. Univariable and multivariable analysis for the prediction of worsening prognosis Univariable analysis Odd ratio 9% CI p-value Age (continuous) 1.023 1.03 1.01 1.9 0.983-1.0 1.00-1.123 1.00-1.02 0.900-2.82 0.2 0.030 0.00 0.120 Multivariable analysis Odd ratio 9% CI p-value 1.09 1.012 1. 1.01-1.19 1.000-1.02 0.89-2. 0.01 0.02 0.129 upstaging 이많았으며, worsening upstaging 군에서그렇지않은군보다임파선침윤이나수술경계부위침범이많은것으로나왔다. 전립선암의치료방법을결정할때, 임상의는대개환자의혈청 PSA와수술전조직검사에서확인된 GS, 그리고직장수지검사나전립선 MRI로결정되는임상병기로분류되는전립선암위험도를참고한다. 3 이중이연구의주제가된중등도위험군의전립선암의치료는환자의기대수명등을고려하여 AS부터 RP까지여러방법중하나로선택될수있다. 하지만최근논문들에서수술전확인된 GS나임상병기가 RP 후시행하는조직검사의결과와상당수에서차이가나고있음을보고하고있다. Cohen 등이 1개의논문과 Lahey clinic medical center에서얻은 1,839 명의자료를분석한연구에서수술전조직검사에서확인된 GS는수술후 조직검사에서 8% 만이일치했으며, GS 인경우에는민감도가 38% 에불과했다고하였다. 9 Richstone 등이국소전립선암환자를대상으로시행한연구에서도수술전 GS 이하였던환자들중 38.% 에서수술후 GS가 이상으로상승하였다. 10 이연구에서흥미로운것은환자나이가 GS 의상승을예측하는인자로나온것인데, 0세이상의환자에서.0% 가이러한결과가나왔던반면 0세미만에서는 3.2% 만이 GS가상승하였다. 게다가임상병기 T2 이하인환자들도 0세이상에서는 0.2% 가 T3 이상으로병기가상승한반면 0세미만에서는 29.3% 만이같은결과를보여환자나이가이러한변화를예측할수있는인자임을시사하였다. 그러나최근다른논문들에서도같은결과가도출되는것은아니다. 포함된환자중 30.0% 가병리등급의상승을보인 Vora 등의연구에서는환자나이가통계적으로유의하지않는것으로나왔으며, 11 총 8명의환자중
10 대한비뇨기종양학술지 : 제 11 권제 3 호 2013 29.% 에서병리등급의상승을보인 Tilki 등의연구에서도환자나이는병리등급의상승여부에따른분석에서큰차이가없다고하였다. 12 마찬가지로 Vora 등의단변수분석에서환자의체질량지수는병리등급의상승을예측할수있었던반면, 전립선부피는그러하지못했는데, Tilki의연구는정반대의결과를보여주었다. 본연구에서는다기관, 후향적연구로서전립선의부피를초음파를이용하여측정하였는데, 측정시시술자에따라차이를보일수있어향후이와같은자료를구축하기위해서는다른객관적측정방법의개발이필요하겠다. 두연구에서환자의수술전인자중병리등급의상승을예측할수있는인자로같은결론이나온것은혈청 PSA 뿐이었으나이결과역시우리의분석과는차이가있다. 전립선암의진단은 PSA 사용이널리퍼지면서지난 10년간크게증가하고있으며이에따라저위험군전립선암의진단도늘어나고있다. 13 비뇨기과의사가이러한환자들에서과도한치료를피하고적절한치료를선택하는것은환자의삶의질향상뿐만아니라사회적비용감소를위해서필요하다. 현재저위험군전립선암의치료는 AS와근치적치료간의치료결과가큰차이가없어 AS를시행해야된다는의견과 AS로인해적절한치료를받을기회를놓칠수있으므로처음부터적극적인치료를해야된다는의견을지지하는연구들이꾸준히발표되고있으며, 1-1 이에따라이전보다저위험군전립선암의치료로 AS를시행하는근거가점차많아지고있다. 18 또한최근몇몇연구들은중등도위험군에서도 AS를적극적으로고려해야한다고주장도있다. 19 저위험군환자 381명과중등도위험군환자 128명에게 AS를시행한 Bul 등의연구는.년간의추적관찰결과, 추정된 10년전체생존률은유의한차이를보이지만 (9.0% vs.% p=0.003), 10년질병특이생존률은 99.1% 와 9.1% 로두군에서큰차이가없으므로 (p=0.), 중등도위험군에서도 AS를고려해야한다고주장하였다. 20 또 Wilt 등이발표한논문에서는중등도위험군환자를포함하는국소전립선암환자들의 10년간추적관찰에서 RP와추적관찰을시행한군의사망률의차이가 3% 미만이라고보고하였다. 21 그러나본연구에서수술전중등도위험군으로분류되었던환자중 2.% 가수술후병리학적검사에서고위험군으로재평가되었다. 이러한차이는전립선암이진단된시점부터수술이시행될때까지지연되는기간동안진행했기때문이라고생각될수도있지만, Freedland 등 22 의연구결과에서볼수있듯이조직검사시점부터수술까지소요되는시간이수술후전립선암의병기나예후와는관계가없음을고려한다면한국인을포함한아시아인에서는서구인과다른양상을보인다고생각할수있다. Chun 등은이러한불일 치, 즉수술전과수술후의전립선암위험도가차이가나는것은수술전시행하는전립선조직검사나전립선 MRI, 직장수지검사의한계라고지적하고있다. 23 우리의연구에는몇가지제한점이있다. 다기관연구로서다섯개의병원에서환자의정보를모았기때문에조직검사의해석이나전립선 MRI의판독, RP의시행등이단일시술자에게시행되지못하여결과에영향을주었을수도있다. 또추적관찰기간이수술시행후생존률을반영할정도로충분하지못해이러한환자들에서보일수있는임상경과의차이를직접적으로비교하지는못했다. 그러나서구와다른양상을보이는한국인을대상으로한연구로중등도위험군의전립선암환자의치료선택에도움을줄수있는결과라고생각한다. 결 본연구에서수술전평가에서중등도위험군전립선암으로분류되었던환자중 2.% 가수술후고위험군환자로재평가되었다. 환자의임상적, 병리적인자중혈청 PSA와 %positive biopsy core의증가는이러한재평가를유의하게예측할수있는인자였다. 적용되는치료방법이다양한중등도위험군전립선암환자의치료방법을결정할때이러한결과를반드시고려하여야할것으로생각한다. 론 REFERENCES 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;1:0-90 2. Jung KW, Won YJ, Kong HJ, Oh CM, Shin A, Lee JS. Survival of Korean adult cancer patients by stage at diagnosis, 200-2010: National Cancer Registry Study. Cancer Res Treat 2013;:12-1 3. Mohler JL, Armstrong AJ, Bahnson RR, Boston B, Busby JE, D Amico AV. Prostate cancer, Version 3.2012: featured updates to the NCCN guidelines. J Natl Compr Canc Netw 2012;10:1081-. Cohen MS, Hanley RS, Kurteva T. Comparing the Gleason prostate biopsy and Gleason prostatectomy grading system: the Lahey clinic medical center experience and an international meta-analysis. Eur Urol 2008;:31-81. Bostwick DG. Gleason grading of prostatic needle biopsies. Correlation with grade in 31 matched prostatectomies. Am J Surg Pathol 199;18:9-803. Kulkarni GS, Lockwood G, Evans A, Toi A, Trachtenberg J, Jewett MA, et al. Clinical predictors of Gleason score upgrading: implications for patients considering watchful waiting, active surveillance, or brachtherapy. Cancer 200;109:232-8
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