Original Paper. Urol Int 2013;90: DOI: /

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1 Urologia Internationalis Original Paer Received: June 28, 212 Acceted: October 15, 212 Published online: February 5, 213 Incidence of Ugrading and Ustaging in Patients with Low-Volume Gleason Score 3+4 Prostate Cancers at Biosy: Finding a New Grou Eligible for Active Surveillance Hee Jung Park a, b Yun-Sok Ha a, c Sung Yul Park b Yong Tae Kim b Tchun Yong Lee b Jeong Hyun Kim d Dong-Hyeon Lee e Wun-Jae Kim c Isaac Yi Kim a a Section of Urologic Oncology and Dean and Betty Gallo Prostate Cancer Center, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, N.J., USA; b Deartment of Urology, Hanyang University College of Medicine, Seoul, c Deartment of Urology, Chungbuk National University College of Medicine, Cheongju, d Deartment of Urology, School of Medicine, Kangwon National University, Chuncheon, and e Deartment of Urology, Ewha Women s University, Seoul, Korea Key Words Prostate cancer Active surveillance Gleason score 3+4 Radical rostatectomy Abstract Introduction: The aim of this study was to identify atients with low-volume Gleason score 3+4 (GS3+4) rostate cancer (PCa) who may be candidates for active surveillance (AS) by analyzing the incidence of ugrading and ustaging following radical rostatectomy (RP). Patients and Methods: Of 97 atients who underwent RP at our institute over the last 5 years, 66 men diagnosed with low-volume GS3+4 PCa at needle biosy were identified. The incidence of ustaging and ugrading was assessed. Results: The overall rate of ugrading and ustaging was 31.8 and 25.6%, resectively. Preoerative PSA levels were significantly higher in atients who were ugraded ( =.15). The otimal reoerative PSA cutoff level for the rediction of ugrading was 4.73 ng/ml (sensitivity 85.7%, secificity 57.8%). Patients with <15% of maximum cores ositive had significantly lower ustaging rate than those with >15% of maximum cores ositive ( =.35). Clinical stage and number of ositive cores had marginal association with ugrading and ustaging statistically ( =.61 and.81, resectively). Conclusions: In atients with low-volume GS3+4 PCa at biosy, underestimation may be effectively avoided when we select atients with PSA <4.73 and % maximum cancer involvement on ositive cores <15%. Coyright 213 S. Karger AG, Basel Introduction Because rostate cancer (PCa) usually has a rolonged natural history, there is a significant controversy concerning the otimal treatment. Radical rostatectomy (RP) has long been recognized as the most definitive treatment for localized PCa while radiotheray has shown Hee Jung Park and Yun-Sok Ha contributed equally to this work. Address all corresondence to: Wun-Jae Kim, M.D. PhD. Deartment of Urology, Chungbuk National University 62, Kaeshin-dong, Heungduk-ku Cheongju, Chungbuk, (South Korea) wjkim@chungbuk.ac.kr karger@karger.com S. Karger AG, Basel /13/93 31$38./ Isaac Yi Kim, MD, PhD Section of Urologic Oncology and Dean and Betty Gallo Prostate Cancer Center The Cancer Institute of New Jersey 195 Little Albany, New Brunswick, NJ 893 (USA) kimiy@umdnj.edu

2 Table 1. Preoerative characteristics of atients with and without ustaging on athologic secimens Table 2. Preoerative characteristics of atients with and without GS ugrading on athologic secimens Preoerative factors Ustaging ( ) (n = 49) Ustaging (+) (n = 17) Preoerative factors Ugrade ( ) (n = 45) Ugrade (+) (n = 21) Age, years * BMI, kg/m * Preoerative serum PSA, ng/ml * * Two-samle t test. Age, years * BMI, kg/m * Preoerative serum PSA, ng/ml * * Two-samle t test. accetable efficacy. More recently though, active surveillance (AS) has emerged as a viable treatment otion for men with tumors of low-risk otential [1 5]. Clear benefits of AS are the reduction of treatment-related morbidities and cost-effectiveness [6]. Gleason score (GS) is an imortant redictor outcome in PCa atients. While atients with GS7 PCa have long been considered to have a more aggressive disease course than GS 6 tumors, GS7 tumors are heterogeneous in their biologic behavior. Several reorts have reorted that GS4+3 cancers have a threefold increase in lethal outcomes comared to GS3+4 cancers; simultaneously, a significant difference in recurrence-free survival rates was found between them [7, 8]. In this regard, some men with GS3+4 cancers may have a more indolent course. Nevertheless, no studies to date have studied whether exanding the criteria for AS to GS3+4 PCa may be safe or viable. The objective of this study was to examine the athologic outcomes in men with GS3+4 PCa who underwent RP and to identify reoerative factors including biosy features that imact the incidence of ugrading and ustaging. These results in turn may aid in exanding the AS rotocols to atients with low-risk GS3+4 tumor at initial diagnosis on the needle biosy secimens. Patients and Methods Patients After obtaining institutional review board aroval, the data of 97 atients who had at least 12 core biosies and underwent radical RP at the Cancer Institute of New Jersey over the last 5 years were analyzed retrosectively. All biosy and RP secimens were reviewed by a genitourinary athologist. Of the 97 men, 66 with a low-volume GS3+4 PCa defined as 3 or less cores ositive, ercentage of maximum cores <5%, and clinical stage T2a or less were enrolled in this study. Pathologic stage and GS were examined ostoeratively. Patients with follow-u <3 months or those with the total number of biosy cores taken <12 were excluded. Biochemical recurrence was defined as three consecutive rises in PSA >.2 ng/ml. Ustaging of PCa was defined as athologic stage T3 T4, and ugrading as the athologic GS 7 (4+3). Statistical Analysis Statistical analysis was erformed by use of Student s t test for continuous variables and the Pearson χ 2 test and Fisher s exact test for categorical variables. A receiver-oerating characteristics (ROC) curve was used to determine the otimal PSA cutoff yielding the highest combined sensitivity and secificity. The software used for statistical analysis was SPSS version 12. (SPSS, Inc., Chicago, Ill., USA), and a value <.5 was considered statistically significant. R e s u l t s The mean age, body mass index (BMI) and PSA level of the enrolled atients were 6.47 years, kg/m 2 and 5.44 ng/ml, resectively. During the follow-u (median 39 months, range 3 66 months), biochemical recurrence occurred in 3 atients. The overall ustaged rate was 25.6% (17 of 66 atients) ( table 1 ) while the ugraded rate was 31.8% (21 of 66 atients) ( table 2 ). None of the reoerative variables showed any statistically significant difference between the non-ustaged and ustaged grous. However, reoerative serum PSA levels were significantly higher in atients who were ugraded than those who did not ( table 2 ) ( =.15). The detailed comarison of the biosy features between atients who were ustaged versus non-ustaged on ostsurgical athologic analysis is shown in tables 3 and 4. Although there was no statistically significant difference in the clinical stage between the two grous, there was a marginal association between the number of osi- 32 Park /Ha /Park /Kim /Lee /Kim /Lee /Kim / Kim

3 Table 3. Comarison of biosy factors in atients with and without ustaging on athologic secimens Table 4. Comarison of biosy factors in atients with and without ugrading on athologic secimens Biosy factors Ustaging ( ) (n = 49) Ustaging (+) (n = 17) Biosy factors Ugrade ( ) (n = 45) Ugrade (+) (n = 21) Number of ositive cores out of 12.81* Single core 32 (82.1%) 7 (17.9%) 2 3 cores 17 (63.%) 1 (37.%) Maximum ercentage of biosy cores.35* <15% 26 (86.7%) 4 (13.3%) 15% 23 (63.9%) 13 (36.1%) Clinical stage 1.** T1c 44 (75.9%) 14 (24.1%) T2a 5 (71.4%) 2 (28.6%) * Pearson χ 2 test. ** Fisher s exact test. Number of ositive cores out of * Single core 28 (71.8%) 11 (28.2%) 2 3 cores 17 (63.%) 1 (27.%) Maximum ercentage of biosy cores.89* <15% 2 (66.7%) 1 (33.3%) 15% 25 (69.4%) 11 (3.6%) Clinical stage.61** T1c 42 (72.4%) 16 (27.6%) T2a 3 (37.5%) 5 (62.5%) * Pearson χ 2 test. ** Fisher s exact test. Ustaging rate (%) =.28 Ugrading rate (%) =.16 Color version available online a PSA<4 4 PSA<6 6 PSA<8 PSA 8 b PSA<4 4 PSA<6 6 PSA<8 PSA 8 Fig. 1. Ustaging ( a ) and ugrading ( b ) rate according to reoerative serum PSA level. value: linear-by-linear association. tive cores and the risk of ustaging ( =.81). More imortantly, atients with <15% maximum cores ositive for cancer had significantly lower ustaging rate than those with >15% maximum cores ( =.35). When the biosy results between atients who were ugraded versus non-ugraded following RP were comared, there were no statistically significant differences in the number of ositive cores or the maximum ercentage of ositive cores; however, a marginal association between the clinical stage and ugrading rate was seen ( =.61). Since reoerative PSA levels correlated with the rate of ugrading, we next examined the effect of varying PSA cutoffs on the overall ercentage of ugrading and ustaging. Although lowering the PSA threshold decreased the rate of ustaging, this change was not statistically significant ( fig. 1 a). In contrast, ugrading rate according to reoerative serum PSA level had a distinctive linear significance ( =.16) ( fig. 1 b). Figure 2 shows the ROC curve to calculate the otimal cutoff value of the reoerative serum PSA level for rediction of ugrade. A PSA level >4.73 ng/ml was shown to be a redictive arameter for ugrading (sensitivity 85.7%, secificity 57.8%). Discussion Results of the resent study demonstrated that the overall rate of ustaging and ugrading in atients with low-volume GS3+4 PCa was 25.6 and 31.8%, resectively. When risk factors that redicted either ustaging or ugrading were analyzed, reoerative PSA level >4.73 ng/ ml and % maximum cores ositive >15% were identified. Active Surveillance Criteria in Low-Volume GS3+4 Prostate Cancer 33

4 Sensitivity Secificity Fig. 2. ROC of otimal PSA values for ugrading: AUC.757, 95% CI The major challenge of managing localized PCa is to distinguish atients with clinically relevant cancers from those with indolent disease. AS is a management strategy that offers atients the hoe of avoiding unnecessary treatment without significantly affecting their long-term survival. Indeed, it has been reorted that in this age of information technology, most PCa atients are very familiar with the various side effects of active treatment [9, 1]. This information, in turn, leads to anxiety and desire for the least invasive treatment. Historically, GS3+4 PCa has been classified as an intermediate-risk disease. Accordingly, commonly used current guidelines for AS exclude GS3+4 PCa. Secifically, AS guidelines from the National Cancer Institute, the Euroean Association of Urology and the University of California San Francisco exclude atients with GS3+4 PCa. Consistent with this view, our recently ublished institutional criteria also exclude these atients from AS [11]. This said, the recently udated University of Toronto AS cohort comosed of 45 men included GS3+4 cancer. Unfortunately, the outcomes of this study were not exlicitly stratified based on GS [12]. More recently though, a reort from University of California San Francisco identified 9 men considered to be intermediate risk (GS3+4 and/or higher PSA level) [3]. In this cohort, the risk of being ustaged after surgery between the intermediate- and low-risk grou was not statistically significant. Therefore, these ublications Color version available online suggest that some GS3+4 PCa may be classified as lowrisk disease. In the context of ustaging, a higher ercentage of maximal biosy cores ( 15%) increased the rate of ustaging in GS3+4 atients. This observation is consistent with revious ublications which have suggested that a maximal ercentage of cancer in biosy cores is a redictable arameter of athologic outcomes [13]. Accordingly, guidelines from the National Cancer Institute and Euroean Association of Urology included this arameter ( 5% ositive cores) while the University of California San Francisco rotocol included a stricter cutoff ( 33% ositive cores) [14, 15]. In contrast, a higher number of ositive cores demonstrated only a trend for an increased rate of ustaging ( =.81). In terms of ugrading, clinical stage T2a was more frequently observed in the ugraded grou than the non-ugraded grou. However, this association between clinical stage and the rate of ugrading was not statistically significant ( =.61). Analyzing the reoerative factors, the PSA level was significantly higher in the ugraded grou. This observation is consistent with the reorts ublished by Freedland et al. [16] and Tilki et al. [17] who have demonstrated that a high PSA level is associated with ugrading of the GS. Using the ROC analysis, the otimal cutoff value for redicting the risk of ugrading in the resent study was 4.73 ng/ ml (sensitivity 85.7%, secificity 57.8%). These results collectively suggest that the AS criteria for men with GS3+4 PCa should be more rigorous than that for men with GS3+3 PCa. Not surrisingly, the ustaging rate in atients with low-volume GS3+4 PCa is considerably higher than the ublished rates of ustaging in atients with GS3+3 PCa who meet the conventional AS criteria. Secifically, in the resent study, the frequency of ustaging was 25.76%. We have reviously reorted ustaging rates of % in men who fulfilled the AS criteria [11]. In contrast to the ustaging risk, the rate of the ugrading reorted rate in this study is not significantly different from the ublished studies as the ugrading rate in our cohort was 31.8%. Previously, Moussa et al. [18] reorted that 26.8% of atients with GS3+4 cancers were ugraded after RP. Notwithstanding the ugrading risk, the ustaging rate of 25.76% in the resent cohort suggests the need for imroving the retreatment assessment in PCa atients considering AS. At the same time, we are exloring the efficacy of endorectal MRI. It should be noted that there are several limitations to the resent study. First, the data were analyzed retrosectively. Second, the samle size is relatively low. With a 34 Park /Ha /Park /Kim /Lee /Kim /Lee /Kim / Kim

5 larger cohort, it is ossible that both the tumor stage and the number of ositive biosy cores may also demonstrate a redictive value in the resent context. Desite these weaknesses the results of the resent study are consistent with the roosal that AS may be a viable otion in some atients with a low-volume GS3+4 PCa. Currently, we have initiated a rosective cohort study to test this concet. In atients with a low-volume GS3+4 PCa, the risk of ustaging and ugrading was 25.6 and 31.8%, resectively. The otimal reoerative criteria for redicting ugrading and ustaging were PSA <4.73 and % maximum ositive cores <15%. Using these additional criteria, a rosective study is underway to investigate the safety of AS in atients with a low-volume GS3+4 PCa at the time of biosy. Acknowledgements This work has been suorted in art by generous grants from the Tanzman Foundation, Jon Runyan s Score for the Cure, and by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( ) and by a grant from the Next-Generation BioGreen 21 Program (No. PJ ), Rural Develoment Administration, Reublic of Korea. References 1 Dall Era MA, Cooerberg MR, Chan JM, Davies BJ, Albertsen PC, Klotz LH, Warlick CA, Holmberg L, Bailey DE Jr, Wallace ME, Kantoff PW, Carroll PR: Active surveillance for early-stage rostate cancer: Review of the current literature. 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