Asian Journal of Andrology (2017) 19,

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1 (2017) 19, AJA, SIMM & SJTU. All rights reserved X Prostte Cncer Open Access ORIGINAL ARTICLE Refining the Americn Urologicl Assocition nd Americn Society for Rdition Oncology guideline for djuvnt rdiotherpy fter rdicl prosttectomy using the pthologic Gleson score Wn Song 1,2, Young Suk Kwon 1, Seong Soo Jeon 2, Isc Yi Kim 1 Recently, it hs been suggested tht the guideline for djuvnt rdiotherpy (ART) following rdicl prosttectomy (RP) sponsored by the Americn Urologicl Assocition nd Americn Society for Rdition Oncology (AUA/ASTRO) my result in significnt overtretment. Thus, the objective of the present study ws to refine the AUA/ASTRO guideline for ART in ptients t risk for biochemicl recurrence (BCR) fter RP. To this end, we reviewed our prospectively mintined dtbse nd selected 193 ptients who met the AUA/ASTRO ART criteri. With medin follow up of 24.0 months, BCR rte ws 17.6% (34/193). When strtified by the Gleson score, BCR rte in men with Gleson score 6 ws 6.8%. There ws no significnt ssocition between BCR free survivl nd surgicl mrgin (P = 0.690) nd pthologic stge (P = 0.353) in ptients with the Gleson score 6. However, in ptients with positive surgicl mrgins (PSMs)/pthologic stge T3, there ws significnt difference in BCR free survivl ccording to Gleson score ( 7 vs 8 10, P = 0.047). Multivrite Cox regression nlysis demonstrted tht pthologic stge T3 (HR = 2.106; P = 0.018), PSMs (HR = 2.411; P = 0.003), nd pthologic Gleson score 8 10 (HR = 4.715; P < 0.001) were independent predictors of BCR fter RP. Therefore, in ddition to pthologic stge T3 nd PSMs, Gleson score 8 10 predicts BCR fter RP. In ptients with Gleson score 6, observtion rther thn ART my be more pproprite regrdless of stge nd surgicl mrgin sttus. (2017) 19, 20 25; doi: / X ; published online: 27 November 2015 Keywords: djuvnt rdiotherpy; biochemicl recurrence; rdicl prosttectomy INTRODUCTION Rdicl prosttectomy (RP) is one of the most effective curtive tretment options for ptients with loclized prostte cncer (PC). 1,2 However, it is estimted tht pproximtely 30% of ptients experience biochemicl recurrence (BCR) fter RP within 10 yers. 3,4 Moreover, the rte of BCR incresed to 40% 60% in men with dverse pthologic findings defined s positive surgicl mrgin (PSM), extrcpsulr extension (ECE), seminl vesicle invsion (SVI), or lymph node invsion (LNI). 5,6 Without dditionl tretment, most ptients with BCR re likely to develop distnt metstsis nd cncer relted deth. Becuse BCR predicts clinicl disese progression, the Americn Urologicl Assocition (AUA) nd Americn Society for Rdition Oncology (ASTRO) jointly relesed guideline for djuvnt rdiotherpy (ART) to decrese the risk of BCR in high risk ptients. The AUA/ASTRO guideline recommended tht ptients with dverse pthologic findings including SVI, PSM, nd extrprosttic extension (EPE) should be informed tht ART, compred to RP only, reduces the risk of BCR, locl recurrence, nd clinicl progression of cncer. 7 These recommendtions re minly bsed on three prospective, rndomized trils tht suggested tht ART my hve fvorble impct on BCR nd locl recurrence for ptients with pthologiclly nonorgn confined PC nd/or PSMs However, there is controversy on the impct of ART on metstsis free survivl nd overll survivl though Europen Orgniztion for Reserch nd Tretment of Cncer (EORTC) tril demonstrted tht clinicl progression free survivl ws improved with ART. Indeed, the AUA/ASTRO guideline on ART cknowledges tht the impct of ART on subsequent metstses nd overll survivl is less cler. 7 Consistent with this uncertinty concerning the effect of ART on survivl outcome, mtched cse control study demonstrted tht ART did not improve rtes of overll nd cncer specific survivl. 11 Thus, the universl doption of ART in ptients with dverse pthologic findings likely represents overtretment in mny men. Disregrding the potentil clinicl benefit of ART, there is concern mong urologists regrding the toxicity of rdiotherpy. Specificlly, ART fter RP showed twice s mny grde III toxicities s RP lone. 8,9 Thus, it is not surprising tht recent study on the pttern of cre nlysis reveled tht <20% of ptients with dverse pthologic findings received ART Section of Urologic Oncology, Rutgers Cncer Institute of New Jersey, Rutgers, The Stte University of New Jersey, New Brunswick, NJ 08903, USA; 2 Deprtment of Urology, Smsung Medicl Center, Sungkyunkwn University School of Medicine, Seoul, South Kore. Correspondence: Prof. IY Kim (kimiy@cinj.rutgers.edu) or Prof. SS Jeon (seongsoo.jeon@smsung.com) Received: 31 Jnury 2015; Revised: 15 April 2015; Accepted: 06 My 2015

2 21 Given this controversy, it is importnt to nlyze the AUA/ASTRO guideline for ART to further clrify the role of ART nd to reduce excessive tretment. In this frmework, our group is focused on further refining the inclusion criteri of ART. We hve previously reported tht the AUA/ASTRO guideline on ART fter RP is overly brod s only 16.6% of the ptients who met the inclusion criteri for ART developed BCR. 13 In this study, we ssessed the risk of BCR fter incorporting the pthologic Gleson score into the current AUA/ASTRO guideline. MATERIALS AND METHODS Ptients This study ws pproved by the Institutionl Review Bord of Rutgers, The Stte University of New Jersey (IRB No: ). To dte, more thn 1300 cses of robot ssisted rdicl prosttectomy (RARP) hve been performed t the Rutgers Cncer Institute of New Jersey, New Brunswick, NJ using the dvinci Surgicl System (Intuitive Surgicl, Sunnyvle, CA, USA) from We retrospectively reviewed the prospectively mintined dtbse of the first 702 ptients who underwent RARP between Jnury 2006 nd July Of 702 ptients, 30 ptients were excluded due to missing pthologic informtion (8), loss of follow up (5), nd not chieving prostte specific ntigen (PSA) ndir to undetectble levels defined s serum PSA level <0.1 ng ml 1 on the first follow up visit fter RP (17). None of the remining 672 ptients hd received neodjuvnt or djuvnt tretment. High risk pthologic risk fetures were determined using the AUA/ASTRO guideline for ART. Bseline chrcteristics including ge nd preopertive PSA, pthologic stge, surgicl mrgin sttus, nd Gleson score were nlyzed. Ptients were strtified into subgroups bsed on dverse pthologic findings nd Gleson score. BCR ws defined s two consecutive rises in PSA with the lst PSA 0.2 ng ml 1. Surgery All surgicl procedures were conducted vi the trnsperitonel pproch. Pelvic lymph node dissection ws performed ccording to the Ntionl Comprehensive Cncer Network (NCCN) guideline t the time of the surgery. 14,15 Surgicl drins were not routinely used. Ptients were monitored every 3 months for the first yer, every 6 months for the second yer, nd yerly therefter with physicl exmintion nd serum PSA level. Sttisticl nlysis Independent smple t test ws used to compre the continuous vribles. Surgicl mrgin sttus, pthologic stge, nd Gleson score were nlyzed using the Person s Chi squre test. Kpln Meier survivl nlysis ws used to ssess BCR free survivl, nd the log rnk test ws pplied to compre survivl rtes of subgroups. Univrite nd multivrite Cox proportionl hzrd models were utilized to identify fctors predicting BCR. All sttisticl nlyses were performed with the IBM SPSS version 20.0 (IBM Corp. Armonk, NY, USA) nd two sided P < 0.05 ws considered sttisticlly significnt. RESULTS Ptient demogrphics Descriptive sttistics of the 672 ptients included in this study re summrized in Tble 1. The medin follow up ws 24 months. The men ge ws 59.1 yers nd men preopertive PSA ws 6.0 ng ml 1. The clinicopthologicl chrcteristics ssocited with BCR were ge, preopertive PSA, surgicl mrgin sttus, pthologic stge, nd Tble 1: Clinicopthologic chrcteristics of 672 ptients who underwent robot ssisted rdicl prosttectomy Vribles Age, yers Totl (n=672) (%) Negtive (n=615) BCR d (%) Positive (n=57) Men±s.d. e 59.1± ± ± Rnge Preopertive PSA c (ng ml 1 ) Men±s.d. e 6.0± ± ± Rnge Pthologic Gleson score (45.2) 291 (47.3) 13 (22.8) <0.001 b (42.3) 265 (43.1) 19 (33.3) (12.5) 59 (9.6) 25 (43.9) Pthologic stge T2 533 (79.3) 506 (82.3) 27 (47.4) <0.001 b T3 120 (17.9) 95 (15.4) 25 (43.9) T3b 19 (2.8) 14 (2.3) 5 (8.7) Surgicl mrgin Negtive 568 (84.5) 532 (86.5) 36 (63.2) <0.001 b Positive 104 (15.5) 83 (13.5) 21 (36.8) Prostte volume (ml) Men±s.d. e 47.5± ± ± Rnge Independent smple t test; b Person s Chi squre test. c PSA: prostte specific ntigen; d BCR: biochemicl recurrence; e s.d.: stndrd devition pthologic Gleson score (P < 0.05). Consequently, higher rte of dverse pthologic findings nd greter percentge of Gleson score 8 10 were present in the BCR group. Pthologic prmeters ssocited with BCR free survivl Of the 672 ptients, 139 (20.7%) hd pthologic stge T3. The overll PSMs rte ws 15.5% (104/672), nd pthologic Gleson score 8 10 ws found in 84 (12.5%) men. The overll BCR rte in this cohort ws 8.5% (57/672). There were notble differences in BCR free survivl with respect to pthologic stge, surgicl mrgin sttus, nd pthologic Gleson score ( T2 vs T3, negtive SM vs positive SM, nd 6 7 vs 8 10, ll P < 0.001, respectively). Bsed on the AUA/ASTRO ART inclusion criteri, dverse pthologic findings were found in 193 ptients; of these ptients, 34 (17.6%) developed BCR. Of the remining 479 ptients who hd no dverse pthologic findings, only 23 (4.8%) ptients showed BCR. When ptients in this cohort were strtified by pthologic Gleson score, BCR rte in men with Gleson 6 ws 4.3% (13/304) in the overll group nd 6.8% (3/44) in the subgroup with dverse pthologic fetures. Mrgin sttus strtified by pthologic stge nd pthologic Gleson score As n initil ttempt to identify men who will likely benefit the most from ART, we renlyzed the dt fter subgrouping ptients bsed on the combintion of surgicl mrgin sttus, pthologic stge, nd pthologic Gleson score. Kpln Meier nlysis ws gin used to evlute BCR free survivl rtes mong the subgroups. In ptients with PSMs, there were differences in BCR free survivl ccording to pthologic stge (P = 0.001) (Figure 1, left pnel) nd Gleson score (P < 0.001) (Figure 1, right pnel). The 5 yer BCR free survivl rte in ptients with PSM/pthologic stge T3 nd PSM/Gleson score 8 10 ws 34.2% nd 22.2%, respectively. In the context of negtive surgicl mrgin, there were lso differences P

3 22 in BCR free survivl ccording to pthologic stge nd Gleson score (Figure 1b). Pthologic stge strtified by surgicl mrgin sttus nd pthologic Gleson score In ptients with pthologic stge T2, there ws no difference in BCR free survivl with regrd to surgicl mrgin sttus (P = 0.267) (Figure 1c, left pnel); however, there ws difference ccording to Gleson score (P = 0.011) (Figure 1c, right pnel). In ptients with pthologic stge T3, there were differences in BCR free survivl with regrd to surgicl mrgin nd Gleson score (P = nd P < 0.001, respectively) (Figure 1d). The 5 yer estimted BCR free survivl rte in ptients with pthologic stge T3 nd Gleson score 8 10 ws 43.4%. b c Figure 1: Kpln Meier curves depicting BCR free survivl in ptients with () positive surgicl mrgin strtified by pthologic stge (Left) nd pthologic Gleson score (Right), (b) negtive surgicl mrgin strtified by pthologic stge (Left) nd pthologic Gleson score (Right), nd (c) pthologic stge T2 strtified by surgicl mrgin sttus (Left) nd pthologic Gleson score (Right) (d) pthologic stge T3 strtified by surgicl mrgin sttus (Left) nd pthologic Gleson score (Right). The results demonstrte tht incorporting pthologic Gleson score further strtifies ptients with PSM or pthologic stge T3. BCR: biochemicl recurrence; PSM: positive surgicl mrgin. d

4 23 Pthologic Gleson score strtified by surgicl mrgin nd pthologic stge Since pthologic Gleson score is not prt of the AUA/ASTRO ART guideline criteri, we next studied the impct of surgicl mrgin sttus nd pthologic stge fter strtifying ptients bsed on pthologic Gleson score. In ptients with Gleson score 6, there ws no difference in BCR free survivl with regrd to surgicl mrgin (P = 0.690) nd pthologic stge (P = 0.353) (Figure 2). Furthermore, no difference ws observed between Gleson nd (P = 0.40). However, notble difference in recurrence existed in men with Gleson scores 7 nd 8 10 (P < 0.05 for both) (Figure 2b nd 2c). In summry, Gleson 6 disese, regrdless of its high risk group sttus s indicted by PSM or pthologic stge T3, did not demonstrte ggressive oncologic fetures tht justifies the use of ART. Compring vrious combintions of high risk pthologic prmeters Interestingly, in ptients with PSMs nd Gleson score 8 10, there ws no difference in BCR free survivl with regrd to pthologic stge ( T2 vs T3, P = 0.648). Similrly, in men with pthologic stge T3 nd GS 8 10, there ws no difference in BCR free survivl with regrd to surgicl mrgin sttus (negtive vs positive, P = 0.599). However, in ptients with PSMs nd pthologic stge T3, higher Gleson score ws ssocited with shorter BCR free survivl ( 7 vs 8 10, P = 0.047). b c Figure 2: Kpln Meier curves depicting BCR free survivl in ptients with () pthologic Gleson score of 6 strtified by surgicl mrgin sttus (Left) nd pthologic stging (Right), (b) pthologic Gleson score of 7 strtified by surgicl mrgin sttus (Left) nd pthologic stge (Right) nd (c) pthologic Gleson score of 8 10 strtified by surgicl mrgin sttus (Left) nd pthologic stge (Right). In men with pthologic Gleson score 6, PSM or pthologic stges did not increse risk of biochemicl recurrence. BCR: biochemicl recurrence; PSM: positive surgicl mrgin.

5 24 Therefore, the subpopultion with Gleson 8 10 nd either PSMs or pthologic stge T3 hd cler indiction for ART. Cox proportionl hzrd regression nlysis Cox proportionl hzrd regression nlysis ws used to ssess the prognostic fctors for BCR fter RP. On univrite nlysis, ge, preopertive PSA, pthologic stge, surgicl mrgin sttus, nd pthologic Gleson score were ssocited with incresed risk of BCR (P < 0.05). On multivrite nlysis, pthologic stge T3 (P = 0.018, hzrd rtio [HR] 2.106, 95% confidence intervl [CI] ), PSMs (P = 0.003, HR: 2.411, 95% CI: ), nd pthologic Gleson score 8 10 (P < 0.001, HR: 4.715, 95% CI: ) were independent predictors of BCR fter RP (Tble 2). DISCUSSION In the present study, we hve demonstrted tht nonorgn confined disese nd PSMs re ssocited with incresed risk of BCR. However, the overll BCR rte in these high risk men ws only 17.6% fter medin follow up of 24 months. When Gleson score ws nlyzed, overll BCR rte in men with Gleson score 6 ws 4.3%. More importntly, in men with Gleson score 6 nd dverse pthologic fetures bsed on the AUA/ASTRO guideline, the BCR rte remined low t 6.8% (3/44). Subsequent nlysis demonstrted tht surgicl mrgin sttus nd pthologic stge did not predict BCR in ptients with the pthologic Gleson score 6 (P = nd P = 0.353, respectively). However, in ptients with PSMs nd pthologic stge T3, higher Gleson score ws ssocited with shorter BCR free survivl ( 7 vs 8 10, P = 0.047). These findings collectively suggest tht Gleson score 6 hs reltively benign clinicl course, nd observtion should be considered regrdless of stge nd surgicl mrgin sttus. In contrst, in men with Gleson score 8 or higher, ART is justified if either PSM or extrprosttic/svi re present. BCR fter RP predicts progression to distnt metstsis nd cncer specific mortlity. 16 Since three rndomized clinicl trils hve demonstrted the beneficil effect of ART on BCR, the AUA nd ASTRO jointly recommended tht ptients with dverse pthologic findings following RP should be offered ART to reduce BCR. However, multiple investigtors hve reported tht the BCR free rte in men with high risk fetures pthologiclly rnges 40% 57.5% over 5 yer period. 5,17,18 Accordingly, the uniform ppliction of AUA/ASTRO s ART guideline is n overtretment in pproximtely hlf of the ptients. Given tht the slvge rte of rdition in men with BCR following surgery in 37% 64%, the benefit of ART on BCR is likely smll. In this context, only 17.6% (34/193) of the men who met the AUA/ ASTRO ART inclusion criteri developed BCR in the current study. In comprison, BCR occurred in 4.8% (23/479) of ptients with negtive surgicl mrgin nd pthologic stge T2. Thus, high risk pthologic fetures s defined by the AUA/ASTRO ART guideline re ssocited with n incresed risk of BCR. Nevertheless, the overll recurrence rte does not justify the cost nd the potentil toxicity of ART. Recently, severl studies hve nlyzed predictive fctors for BCR fter RP These reports hve demonstrted tht preopertive PSA, pthologic stge such s ECE, SVI, PSMs, nd LNI, nd pthologic Gleson score re prognostic fctors. Consistent with these published dt, we hve confirmed tht pthologic stge, surgicl mrgin sttus, nd pthologic Gleson score re importnt prognostic fctors of BCR. Similrly, nomogrms predicting BCR or cncer specific mortlity require Gleson score. 3,22,26 Collectively, these results suggest tht pthologic Gleson score should be considered in selecting the optiml cndidtes for ART. Nevertheless, Gleson score is currently not prt of the AUA/ASTRO guideline for ART. If pthologic Gleson score ws to be dopted s fctor in selecting ptients for ART, high pthologic Gleson score should be considered s one of the inclusion criteri. Not surprisingly, multiple groups hve demonstrted tht the pthologic Gleson score 8 10 tightly correltes with BCR fter RP. 23,24 Wlz et l. 27 nlyzed BCR free survivl ccording to clinicl stge T3, biopsy Gleson score 8, nd preopertive PSA 20.0 ng ml 1. The uthors reported tht biopsy Gleson score 8 showed the worst BCR free survivl rte t 2, 5, nd 10 yers with 58.8%, 39.9%, nd 26.4%, respectively. In the current study, 29.8% (25/84) of the ptients with pthologic Gleson score 8 10 experienced BCR. In ptients with PSMs nd Gleson score 8 10, recurrence occurred in more thn three qurters s the estimted 5 yer BCR free survivl rte ws only 22.2%. In ddition, these ptients with PSMs nd Gleson score 8 10 hd no difference in BCR free survivl with regrd to pthologic stge ( T2 vs T3, P = 0.648). In contrst, the combintion of PSMs nd pthologic stge T3 ws ssocited with the BCR free survivl when strtified by Gleson score ( 7 vs 8 10, P = 0.047). Tken together, these results show tht the presence of pthologic Gleson score 8 10 should be used in counseling ptients considering ART. In contrst to the high pthologic Gleson score, the present study demonstrted no difference in BCR free survivl with regrd to surgicl mrgin (P = 0.690) nd pthologic stge (P = 0.353) in ptients with Tble 2: Uni nd multivrite Cox regression nlyses predicting BCR in 672 prostte cncer ptients who underwent robot ssisted rdicl prosttectomy Vribles Univrite Multivrite Age ( ) Preopertive PSA (ng ml 1 ) >6.0 versus ( ) Pthologic stge HR b (95% CI c ) P HR b (95% CI c ) P T3 versus T ( ) < ( ) Mrgin sttus Positive versus negtive ( ) < ( ) Pthologic Gleson score (Ref d ) (Ref d ) ( ) ( ) ( ) < ( ) <0.001 PSA: prostte specific ntigen; b HR: hzrd rtio; c CI: confidence intervl; d Ref: reference vlue; BCR: biochemicl recurrence

6 25 the pthologic Gleson score 6. This observtion is consistent with the body of literture tht suggests tht Gleson score 6 PC hs reltively indolent course. For exmple, Svdie et l. 28 exmined the ssocition between pthologic Gleson score t the surgicl mrgin nd BCR with medin follow up of 82 months. The results showed tht the 5 yer ctul BCR free survivl for negtive surgicl mrgin nd PSMs with Gleson grde 3 t the mrgin ws 85.6% nd 83.8%, respectively. Therefore, we recommend tht the AUA/ASTRO should consider excluding ll men with the pthologic Gleson score 6 regrdless of the stge nd surgicl mrgin sttus in the context of ART. Despite the potentil clinicl implictions of the present study, there re some limittions. First, this is retrospective, nonrndomized study nd conducted t single institution, thus rising concerns for selection bis. Notwithstnding, this study used prospectively mintined dtbse nd reflects rel clinicl prctice. Second, the follow up period is reltively short nd thus, BCR rte nd the results of multivrite nlysis my be underestimted. It should be pointed out though, tht erly onset of BCR fter RP is ssocited with poor prognosis. Thus, this study likely identifies those who will likely benefit the most from ART. Regrdless, since the short follow up period is mjor limittion, this investigtion should be considered hypothesis generting study. Third, the smple size is reltively smll. In the future, lrge prospective multi institutionl study will be crried out to develop strtifiction system tht will help identify the optiml cndidtes for ART fter RP. CONCLUSION Oncologic outcomes following RP in ptients with dverse pthologic fetures re heterogeneous. Thus, the current AUA/ASTRO guideline on ART my be overly brod nd rises the concern for overtretment. In this regrd, the pthologic Gleson score is n importnt prognostic fctor. The current hypothesis generting study suggests tht ART should be considered in ptients with the pthologic Gleson 8 10 long with nonorgn confined disese or PSM. To the contrry, in ptients with Gleson score 6, observtion rther thn ART my be more prudent regrdless of stge nd surgicl mrgin sttus. A study with longer follow up is necessry to test this hypothesis. AUTHOR CONTRIBUTIONS WS prticipted in the design of the study, sttisticlly nlyzed the dt, nd drfted the mnuscript. YSK reviewed the pertinent literture, revised, nd reformtted the mnuscript. JSS ssisted with the design of the study, conducted the dt cquisition, nd revised the mnuscript for importnt intellectul content. IYK prticipted in the design of the study, conducted the dt cquisition, nd revised the mnuscript criticlly for importnt intellectul content. All uthors red nd pproved the finl mnuscript. COMPETING INTERESTS All uthors declre no competing finncil interests. 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