Management of Localized Kidney Cancer: Calculating Cancer-specific Mortality and Competing Risks of Death for Surgery and Nonsurgical Management

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1 EUROPEAN UROLOGY 6 (14) ville t journl homepge: Kidney Cncer Mngement of Loclized Kidney Cncer: Clculting Cncer-specific Mortlity nd Competing Risks of Deth for Surgery nd Nonsurgicl Mngement Mxine Sun,,1, *, Andres Becker,c,1, Zhe Tin, Florin Roghmnn,d, Firs Adollh,e, Alexndre Lrouche, Pierre I. Krkiewicz,f, Quoc-Dien Trinh,f Cncer Prognostics nd Helth Outcomes Unit, University of Montrel Helth Center, Montrel, Cnd; Deprtment of Pulic Helth, Fculty of Medicine, University of Montrel, Montrel, Cnd; c Mrtini-Clinic, Prostte Cncer Center Hmurg-Eppendorf, Hmurg, Germny; d Deprtment of Urology, Universitätsklinik Mrienhospitl, Herne, Germny; e Deprtment of Urology, Vit-Slute Sn Rffele University, Miln, Itly; f Deprtment of Urology, University of Montrel Helth Center, Montrel, Cnd Article info Article history: Accepted Mrch, 13 Pulished online hed of print on Mrch 27, 13 Keywords: Loclized kidney cncer Nephrectomy Nonsurgicl mngement SEER Astrct Bckground: For elderly individuls with loclized renl cell crcinom (RCC), surgicl intervention remins the primry tretment option ut my not enefit ptients with limited life expectncy. Ojective: To clculte the trde-offs etween surgicl excision nd nonsurgicl mngement (NSM) with respect to competing cuses of mortlity. Design, setting, nd prticipnts: Relying on cohort of Medicre eneficiries, ll ptients with nonmetsttic node-negtive T1 RCC etween 1988 nd were strcted. Intervention: All ptients were treted with prtil nephrectomy (PN), rdicl nephrectomy (RN), or NSM. Outcome mesurements nd sttisticl nlysis: Cncer-specific mortlity (CSM) nd other-cuse mortlity (OCM) rtes were modeled through competing-risks regression methodologies. Instrumentl vrile nlysis ws used to ccount for the potentil ises ssocited with mesured nd unmesured confounders. Results nd limittions: A totl of 9 ptients were identified. In instrumentl vrile nlysis, ptients treted with PN (hzrd rtio [HR]:.; 9% confidence intervl [CI],.24.83; p =.1) or RN (HR:.8; 9% CI,..96; p =.3) hd significntly lower risk of CSM thn those treted with NSM. In sunlyses restricted to ptients 7 yr, the instrumentl vrile nlysis filed to detect ny sttisticlly significnt difference etween PN (HR:.48; p =.1) or RN (HR:.7; p =.1) reltive to NSM with respect to CSM. Similr trends were oserved in T1 RCC only. Conclusions: PN or RN is ssocited with reduction of CSM mong older ptients dignosed with loclized RCC, compred with NSM. The sme enefit filed to rech sttisticl significnce mong ptients 7 yr. The hrms of surgery need to e weighed ginst the mrginl survivl enefit for some ptients. Crown Copyright # 13 Pulished y Elsevier B.V. on ehlf of Europen Assocition of Urology. All rights reserved. 1 Equl contriution. * Corresponding uthor. Cncer Prognostics nd Helth Outcomes Unit, University of Montrel Helth Center, 264 Blvd. Rene-Levesque Est, #228, Montrel (QC), Cnd H2X 1P1. Tel , ext: 3; Fx: E-mil ddress: mcw.sun@umontrel.c (M. Sun) /$ see ck mtter Crown Copyright # 13 Pulished y Elsevier B.V. on ehlf of Europen Assocition of Urology. All rights reserved.

2 236 EUROPEAN UROLOGY 6 (14) Introduction Current mngement of ptients with loclized renl cell crcinom (RCC) 7 cm consists of surgicl excision, preferly prtil nephrectomy (PN) over rdicl nephrectomy (RN) whenever techniclly fesile [1 3]. Alterntively, initil oservtion hs gined considerle precedence in recent yers; the utiliztion rte ws nerly % in 8 reltive to nephrectomy for ptients with T1 RCC [1 4]. The growing cceptnce of oservtion egn when severl reports demonstrted lck of declining mortlity rtes for loclized RCC over time, despite erlier detection resulting from widespred imging use [], therey chllenging the longstnding role of expedient surgicl excision fter RCC dignosis. Previous studies showed tht suspicious tumors grow slowly over time (.3 cm/yr), frequently follow protrcted course (%), nd re unlikely to metstsize (<1%) [6 9]. Further rguments in fvor of initil oservtion include the sustntil proportion of older ptients with cliniclly node-negtive T1 disese nd other-cuse mortlity (OCM) [,11]. Recent dt further confirm the importnce of ctive surveillnce; the dt indicted lck of survivl enefit etween PN or RN reltive to ctive surveillnce mong elderly ptients with cliniclly loclized RCC [12]. Under the light of chnging tretment prdigm for smll renl msses, mny physicins my feel sufficiently ressured y existing dt to recommend oservtion for individuls with limited life expectncy nd/or decresed functionl sttus, while other physicins my feel pprehensive out the potentil risk of n ggressive disese phenotype, thus fvoring surgery to void uncertinties with respect to disese-specific mortlity. We sought to clculte the trde-offs of surgicl intervention (PN or RN) compred with nonsurgicl mngement (NSM) with respect to survivl in lrge smple of ptients with T1 RCC to optimize tretment-relted decision mking. 2. Methods 2.1. Dt source Dt originted from the US Surveillnce Epidemiology nd End Results (SEER) Medicre linked dtse. Medicre provides federlly funded helth insurnce for pproximtely 97% of persons 6 yr in the United Sttes [13]. Linkge to the SEER dtse is complete for pproximtely 94% of ptients [14] Study popultion Between 1988 nd, individuls ged 66 yr with primry dignosis of nonmetsttic RCC, who hd oth Medicre Prt A nd Prt B clims ville, nd who were not enrolled in helth mintennce orgniztion throughout the durtion of the study period were strcted. Only individuls with node-negtive T1 RCC tumors 7 cm of cler cell, ppillry, chromophoe, RCC unspecified, or other (collecting duct, grnulr, medullry, cystic) histologic sutypes were included. Other exclusions consisted of ptients dignosed only t utopsy or on deth certificte, ptients whose originl or current reson for Medicre entitlement ws listed s disility or Medicre sttus code, nd ptients with unknown tumor size. The result ws 9 ssessle individuls for our study Vrile definition Ptients treted within 6 mo of RCC dignosis with PN or RN were identified [,16]. NSM ws defined s the sence of ctive tretment codes (ie, PN, RN, ltive techniques), which resulted in 3271 ssessle individuls. Of those ptients, 114 (3.%) underwent nephrectomy >6 mo fter dignosis. Of those ptients, 29 died of ny cuse, which is.8% of the NSM group. Given their smll numers, such individuls remined in the nlyses despite hving delyed nephrectomy. For ech ptient, ge t dignosis, sex, rce, nd mritl sttus were ssigned using the SEER dt. Socioeconomic sttus ws computed using previously descried methodology [17]. Bseline conditions were mesured through modified version of the Chrlson comoridity index sed on clims 1 yr efore RCC dignosis [18] nd grouped s, 1, nd 2. Tumor size nd Fuhrmn grde were lso considered End points Ptients who died of RCC-specific deth were clssified s cncer-specific mortlity (CSM). Ptients who died of other cuses were clssified s other-cuse mortlity (OCM). Dt on cuse-specific mortlity nd follow-up were ville throughout the end of 7. The durtion of survivl ws mesured s the intervl etween RCC dignosis nd the Medicre dt of mortlity or lst follow-up. 2.. Sttisticl nlyses Two-sided x 2 tests nd Mnn-Whitney tests were used to evlute ssocitions etween tretment type (nephrectomy compred with NSM) nd covrites. To reduce residul confounding due to unmesured ptient nd/or other pertinent chrcteristics, we relied on instrumentl vrile nlysis [19]. The instrument vrile used ws the locl re tretment intensity of surgery (RN nd PN). The instrument vrile ws creted y grouping ptients from the SEER-Medicre dtse ccording to hospitl referrl regions, s developed y the Drtmouth Atls of Helth Cre []. This vrile ws clculted s the proportion of ptients who received surgery in ech helth service re (HSA). Prior to the instrument s use, we ssessed its vlidity y confirming tht the intensity of nephrectomy use ccording to HSA ws highly correlted with receipt of surgery (x 2 test p <.1, multivrile F sttistic >) ut ws not ssocited with survivl in multivrile models (CSM hzrd rtio [HR]:.98, p =.8; OCM HR:.98, p =.4). In primry nlyses, comprtive effectiveness of nephrectomy compred with NSM ws tested through competing risks regression models for prediction of CSM fter djusting for OCM, nd vice vers [21], in the entire cohort nd then mong ptients with exclusively T1 RCC. Finlly, sunlyses were conducted y restricting the cohort to ptients 7 yr [22], ptients without ny secondry mlignncies, ptients dignosed in the yer nd onwrd, nd ptients with T1 RCC who were 7 yr. All sttisticl testing ws two-sided, with level of significnce set t %. Anlyses were performed using the R softwre environment for sttisticl computing nd grphics (v.2..2). 3. Results 3.1. Bseline chrcteristics Of 9 T1 RCC individuls, 3271 (.9%), 1 (9.9%), nd 6273 (9.2%) were treted with NSM, PN, nd RN,

3 EUROPEAN UROLOGY 6 (14) Tle 1 Descriptive chrcteristics of ptients with loclized renl cell crcinom =7 cm treted with nonsurgicl mngement, prtil nephrectomy, nd rdicl nephrectomy * NSM PN RN p vlue High NT use Low NT use p vlue Ptients, no. (%) 3271 (.9) 1 (9.9) 6273 (9.2) 4379 (41.3) 6216 (8.7) NSM, no. (%) 814 (18.6) 27 (39.) <.1 Age, yr <.1.2 Men (medin) 7 (74) 73 (72) 74 (74) 74 (74) 7 (74) IQR Sex, no. (%) <.1 <.1 Mle 1968 (6.2) 6 (8.) 3334 (3.1) 2332 (3.3) 8 (7.7) Femle 13 (39.8) 436 (41.) 2939 (46.9) 47 (46.7) 2631 (42.3) Rce, no. (%) <.1 <.1 White 87 (79.) 888 (84.) 3 (84.7) 383 (88.) 4937 (79.4) Blck 349 (.7) 88 (8.4) 489 (7.8) 419 (9.6) 7 (8.2) Other 3 (.3) 7 (7.1) 469 (7.) 7 (2.4) 762 (12.4) CCI, no. (%) <.1 < (7.9) 8 (34.1) 2288 (36.) 16 (37.8) 39 (3.2) (.) 1 (13.8) 7 (12.) 19 (11.9) 39 (8.7) 2 79 (24.2) 48 (2.1) 32 (1.6) (.4) 2368 (38.1) Socioeconomic sttus, no. (%) <.1 <.1 High 1739 (3.2) 612 (8.2) 2986 (47.6) 72 (47.3) 326 (2.) Low 32 (46.8) 439 (41.8) 3287 (2.4) 27 (2.7) 291 (47.) Mritl sttus, no. (%) <.1 <.1 Mrried 1897 (8.) 693 (6.9) 3829 (61.) 2629 (6.) 379 (61.) Single 226 (6.9) 72 (6.9) 8 (6.) 273 (6.2) 433 (7.) Previously mrried (31.9) 1 (23.9) 1867 (29.8) (29.8) 188 (29.9) Unknown 3 (3.1) (3.3) 169 (2.7) 172 (3.9) 1 (2.2) Tumor size, cm <.1.2 Men (medin) 3.8 (3.) 2.9 (2.7) 4.1 (4.) 3.8 (3.) 3.9 (3.8) IQR Histologicl sutype, no. (%) <.1.2 Cler cell 33 (31.6) 394 (37.) 2289 (36.) 17 (33.3) 29 (36.3) Ppillry 179 (.) 4 (14.7) 372 (.9) 312 (7.1) 393 (6.3) Chromophoe 98 (3.) 68 (6.) 189 (3.) 149 (3.4) 6 (3.3) Other 77 (2.4) 42 (4.) 2 (3.2) 129 (2.9) 192 (3.1) Unspecified 1884 (7.6) 393 (37.4) 3221 (1.3) 2332 (3.3) 3166 (.9) Fuhrmn grde, no. (%) <.1 <.1 I II 14 (41.4) 611 (8.1) 3241 (1.7) 1983 (.3) 3223 (1.9) III IV 339 (.4) 134 (12.7) 776 (12.4) 6 (.4) 793 (12.8) Unknown 78 (48.2) 6 (29.1) 26 (36.) 19 (44.3) 2 (.4) Follow-up, mo, men (medin) 96.6 (81.) (127.) 1.4 (.) (2.) 1.4 (99.) NSM = nonsurgicl mngement; PN = prtil nephrectomy; RN = rdicl nephrectomy; NT = nephrectomy; IQR = interqurtile rnge; CCI = Chrlson comoridity index. * Surveillnce Epidemiology nd End Results (SEER) Medicre linked dtse, respectively (Tle 1). Cliniclly relevnt differences were oserved for tumor size, tumor grde distriution, nd histologic sutypes (ll p <.1). In ptients with one seline comoridity or more, the most common comoridities for NSM, PN, nd RN ptients were dietes (47%, 47%, nd 44%, respectively; p =.1), chronic pulmonry disese (47%, 44%, nd 47%, respectively; p =.3), cererovsculr disese (39%, 28%, nd 31%, respectively; p <.1), peripherl vsculr disese (17%, 16%, nd 14%, respectively; p =.3), nd renl disese (16%, %, nd 14%, respectively; p =.3) Undjusted survivl nlyses In undjusted cumultive incidence mortlity rtes, the - nd 8-yr CSM rtes were.2% nd 11.7% for NSM, 6.7% nd 8.8% for RN, nd 3.1% nd 4.9% for PN, respectively (Fig. 1). For the sme time points, OCM rtes were.4% nd 44.3% for NSM, 22.3% nd 36.8% for RN, nd 17.6% nd 29.% for PN, respectively (Fig. 1). Among T1 RCC individuls, the undjusted -yr nd 8-yr CSM rtes were 7.4% nd 8.% for NSM, 4.% nd.7% for RN, nd 2.6% nd 4.7% for PN, respectively (Fig. 2). For the sme time points, OCM rtes were.% nd.2% for NSM, 21.6% nd 36.2% for RN, nd 16.% nd.6% for PN, respectively (Fig. 2) Two-stge residul competing risks model Bsed on the two-stge residul inclusion model, oth PN (HR:.; 9% confidence intervl [CI],.24.83; p =.1) nd RN (HR:.8; 9% CI,..96; p =.3) were significntly ssocited with lower risk of CSM reltive to NSM (Tle 2). Similrly, oth PN (HR:.1; 9% CI,.37.69; p <.1) nd RN (HR:.9; 9% CI,..79; p =.3) were significntly ssocited with lower risk of OCM reltive to NSM. Similr survivl trends were recorded when the multivrile nlyses were repeted mong ptients with T1 RCC only (Tle 2).

4 238 [(Fig._1)TD$FIG] EUROPEAN UROLOGY 6 (14) [(Fig._2)TD$FIG] RN PN Fig. 1 Cumultive incidence of () cncer-specific mortlity rtes nd () other-cuse mortlity rtes t yr nd 8 yr of follow-up fter nephrectomy (PN) in the entire cohort. The sttisticl significnce compring nephrectomy type nd NSM ws estimted using the Gry p vlue. Error rs indicte 9% confidence intervls. () RN compred with NSM, p =.1; PN compred with NSM, p <.1. () RN compred with NSM, p <.1; PN compred with NSM, p <.1. Fig. 2 Cumultive incidence of () cncer-specific mortlity rtes nd () other-cuse mortlity rtes t yr nd 8 yr of follow-up fter nephrectomy (PN) in ptients with T1 renl cell crcinom. The sttisticl significnce compring nephrectomy type nd NSM ws estimted using the Gry p vlue. Error rs indicte 9% confidence intervls. () RN compred with NSM, p =.1; PN compred with NSM, p <.1. () RN compred with NSM, p <.1; PN compred with NSM, p <.1. Tle 2 Multivrile competing risks regression nlyses estimting the effect of tretment type on the risks of cncer-specific mortlity nd other-cuse mortlity PN vs NSM, HR (CI) p vlue RN vs NSM, HR (CI) p vlue Cncer-specific mortlity Primry nlyses Entire cohort, n = 9. (.24.83).1.8 (..96).3 T1, n = (.18.91).3.47 (.23.98).4 Sunlyses 7 yr, n = (. 1.14).1.7 ( ).1 T1 nd 7 yr, n = ( ).1. ( ).1 RCC only, n = (.13.4).1.48 (.27.8).1 Yer of dignosis, n = 777. (..8) <.1.47 (.26.84).1 Other-cuse mortlity Primry nlyses Entire cohort, n = 9.1 (.37.69) <.1.9 (..79).3 T1, n = (.32.7) <.1.61 (.43.87).6 Sunlyses 7 yr, n = 48. (.36.83).4.61 (.42.89).1 T1 nd 7 yr, n = (.28.77).3.6 (..89).2 RCC only, n = (.31.67) <.1.3 (.37.74) <.1 Yer of dignosis, n = (.29.62) <.1.2 (.37.74) <.1 HR = hzrd rtio; CI = confidence intervl, PN = prtil nephrectomy; NSM = nonsurgicl mngement; RN = rdicl nephrectomy, RCC = renl cell crcinom. All models were sed on two-stge residul inclusion model. Adjustment ws mde for ptient ge, sex, rce, seline comoridities, socioeconomic sttus, mritl sttus, tumor size, histologicl sutype, Fuhrmn grde, nd yer of dignosis. Secondry mlignncies excluded.

5 [(Fig._3)TD$FIG] EUROPEAN UROLOGY 6 (14) [(Fig._4)TD$FIG] RN PN NSM NSM RN RN PN RN PN PN RN PN RN PN Fig. 3 Cumultive incidence of () cncer-specific mortlity rtes nd () other-cuse mortlity rtes t yr nd 8 yr of follow-up fter nephrectomy (PN) in ptients I7 yr. The sttisticl significnce compring nephrectomy type nd NSM ws estimted using the Gry p vlue. Error rs indicte 9% confidence intervls. () RN compred with NSM, p <.1; PN compred with NSM, p <.1. () RN compred with NSM, p <.1; PN compred with NSM, p <.1. Fig. 4 Cumultive incidence of () cncer-specific mortlity rtes nd () other-cuse mortlity rtes t yr nd 8 yr of follow-up fter nephrectomy (PN) in ptients with T1 renl cell crcinom who re I7 yr. The sttisticl significnce compring nephrectomy type nd NSM ws estimted using the Gry p vlue. Error rs indicte 9% confidence intervls. () RN compred with NSM, p =.3; PN compred with NSM, p =.4. () RN compred with NSM, p <.1; PN compred with NSM, p < Sunlyses Sunlyses restricted to ptients 7 yr were conducted to explore the enefit of nephrectomy in this cohort. The -yr nd 8-yr CSM rtes were 14.7% nd 16.2% for NSM, 8.1% nd.% for RN, nd 4.3% nd.2% for PN, respectively (Fig. 3). For the sme time points, OCM rtes were 38.1% nd 4.8% for NSM, 27.6% nd 46.1% for RN, nd.4% nd 38.1% for PN, respectively (Fig. 3). Among individuls with T1 RCC who were 7 yr, the -yr nd 8-yr CSM nd OCM rtes re shown in Figure 4 nd 4. In multivrile nlyses restricted to this sucohort of elderly ptients, neither PN (HR:.48; 9% CI,. 1.14) nor RN (HR:.7; 9% CI, ) (oth p =.1) were ssocited with enefit in CSM compred with NSM (Tle 2). 4. Discussion Tretment options for the mngement of erly-stge RCC re minly surgery (PN or RN) or oservtion [4,23]. The ltter is listed y ntionl guidelines s wht should e the primry considertion mong ptients with decresed life expectncy nd/or competing helth risks [1 3]. For the most prt, it seems tht the urologic community in the United Sttes suscries to this pproch, s recent popultion-sed report showed tht NSM ws chosen over nephrectomy in one of every five ptients dignosed with T1 RCC s of 8 [4]. Given the shifting tretment prdigm of loclized RCC, we sought to evlute CSM nd OCM rtes for nephrectomy compred with NSM nd to clculte the trdeoffs of surgicl mngement compred with NSM. Within Medicre eneficiries, our cohort comprised 9 ptients with T1NM RCC. The mjority of ptients underwent either PN or RN, wheres 3 of individuls underwent NSM. The current report represents the first popultion-sed ssessment compring NSM nd nephrectomy with respect to survivl for loclized kidney cncer mong older individuls, using two-stge residul inclusion pproch in instrumentl vrile nlysis in the context of competing risks regression models. The primry finding of the current study indictes tht nephrectomy ws ssocited with mrginl, though not insignificnt, reduction of CSM reltive to NSM mong older ptients (66 yr) with T1 RCC oth in undjusted nd djusted nlyses. Specificlly, for every ptients treted with NSM, RN, or PN, 11, 8, nd 4 ptients, respectively, died of CSM during 8 yr of follow-up. Similr findings were recorded when the nlyses focused on only

6 2 EUROPEAN UROLOGY 6 (14) ptients with T1 disese, thus confirming the importnce of surgicl excision reltive to NSM in the generl sense. However, such enefit should e weighed ginst the risk of OCM. Specificlly, our results lso indicte tht for every ptients treted with NSM, RN, or PN, 44, 36, nd 29 ptients, respectively, died of OCM during 8 yr of followup. Becuse of the retrospective nture of the study, we my only speculte on the following plusile explntions for such high OCM rtes: (1) After nephrectomy, the reduction in the risk of CSM resulted in n incresed rte of competing-cuse mortlity, or (2) nephrectomy-induced postopertive renl dysfunction leding to crdiovsculrrelted mortlity ws extensive. The first scenrio likely occurred to certin extent ut could not fully explin the sizele proportion of ptients who died of OCM in the nephrectomy group (31%). As such, the second scenrio remins the most likely. Such ssocitions my e the result of the predominnt use of RN in this cohort (9%), which compred with PN hs een shown to e risk fctor of postopertive chronic kidney disese [,16,24,] nd which ers n undisputed ssocition with incresed risk of crdiovsculr-relted deths [26,27]. Indeed, our results showed tht OCM rtes 8 yr fter surgery were 36.2% for RN nd.6% for PN, therey indirectly confirming the second hypothesis. The selection of surgicl cndidtes cnnot e sed solely on chronologicl ge ut should lso consider ptients ility to hndle the sequele of surgery (ie, renl dysfunction, crdiovsculr events). The second prt of our results further sustntites this sttement. Specificlly, in sunlyses, the forementioned enefit in CSM-free survivl ws no longer significnt in multivrile djustment when the popultion ws restricted to ptients 7 yr. For every ptients treted with NSM, RN, or PN, 4, 46, nd 38 ptients, respectively, died of OCM during 8 yr of follow-up. In this setting, two hypotheses my e considered: (1) Hd proper ptient selection of surgicl cndidtes sed on life expectncy nd functionl sttus ensued, nephrectomy would hve resulted in significnt survivl enefit, despite eing n elderly sucohort, nd (2) nephrectomy is lrgely unnecessry in ptients with dvnced ge ecuse of their decresed life expectncy nd decresed seline renl function. In other words, even if ptient selection were dequte, most of these ptients simply would not live long enough to enefit from surgery. Unfortuntely, neither the current popultion-sed study nor n institutionl study cn relily exmine such hypotheses, which should idelly e tested in prospective rndomized tril. However, the results do indicte necessry cution in recommending surgery for ptients >7 yr, s the hrms (risk of OCM) do outweigh the enefits (risk of CSM). The primry limittion of our study pertins to the NSM group, which ws identified y wy of the sence of procedure codes for nephrectomy or other, less invsive tretments (eg, tumor ltion). It is possile tht proportion of such ptients were not ctully following rigorous surveillnce protocol. Indeed, some ptients in the NSM group my ctully strongly contrst with cndidtes for ctive surveillnce in contemporry clinicl prctice. NSM my hve included ptients whose tumors were inoperle despite their eing surgiclly fit cndidtes or ptients who refused to undergo surgery despite eing recommended otherwise. If some ptients were truly under ctive surveillnce, the rigor of surveillnce protocol my hve differed tremendously from one center to nother, s the clinicl mening of NSM fluctuted in ptients dignosed in more historicl yers compred with ptients dignosed in more contemporry yers. Moreover, some NSM ptients (3.%) received delyed nephrectomy. However, s Crispen et l. [28] previously showed, delyed surgicl intervention does not ffect oncologic outcome. The forementioned fctors likely enhnced the heterogeneity of the studied popultion. Consequently, the relince on instrumentl vrile nlysis, lthough not equivlent to rndomiztion, represents n cceptle choice of methodology, given tht it llows the considertion of such unmesured confounders. Tht sid, the use of instrumentl vrile nlysis remins questioned ecuse of its vrile estimted effect nd unverified ssumptions [29]. Therefore, despite dequte sttisticl mens, mple cution is wrrnted in the interprettion of such nlyses, nd the conclusions should not e overstted. The qulity of the dt (ie, tumor extent, histology ssignment) cptured in the SEER-Medicre dtse my e limited. For exmple, wheres the dtse indictes tht 92% of ptients hd positive histologic confirmtion of mlignnt cncer, 17% of NSM ptients hd only n imging dignosis. Assuming tht % of ptients with smll renl mss hve enign histology [8], pproximtely 3.4% of ptients in the NSM group my hve hd nonmlignnt disese. Although this percentge is reltively smll, it certinly correltes with cuse-of-deth issues, in which nonctively treted cncer ptients re more likely to die of CSM just for eing untreted, despite hroring enign pthology. The rel proportion of nonctively treted ptients who die of CSM is difficult to quntify in retrospective dt. However, cuse of deth ws deemed s highly ccurte in previous study []. Finlly, locl nd/or metsttic progression is not relily mesurle in SEER. Such dditionl end points my hve een pertinent.. Conclusions Nephrectomy is ssocited with reduction of CSM reltive to NSM for loclized RCC. In older individuls (7 yr), the enefit of surgery ws not significnt, therey corroorting recommendtions from contemporry guidelines supporting the role of NSM in such ptients. Nonetheless, the dilemm persists, s some older individuls my nonetheless enefit from surgery, nd older ge lone should not e sine qu non for omitting nephrectomy. Author contriutions: Mxine Sun hd full ccess to ll the dt in the study nd tkes responsiility for the integrity of the dt nd the ccurcy of the dt nlysis. Study concept nd design: Sun, Becker, Krkiewicz, Trinh. Acquisition of dt: Sun, Tin. Anlysis nd interprettion of dt: Sun, Becker, Tin, Roghmnn.

7 EUROPEAN UROLOGY 6 (14) Drfting of the mnuscript: Sun, Becker, Adollh. Criticl revision of the mnuscript for importnt intellectul content: Krkiewicz, Trinh. Sttisticl nlysis: Sun, Becker, Tin, Lrouche. Otining funding: None. Administrtive, technicl, or mteril support: None. Supervision: Krkiewicz. Other (specify): None. Finncil disclosures: Mxine Sun certifies tht ll conflicts of interest, including specific finncil interests nd reltionships nd ffilitions relevnt to the suject mtter or mterils discussed in the mnuscript (eg, employment/ffilition, grnts or funding, consultncies, honorri, stock ownership or options, expert testimony, roylties, or ptents filed, received, or pending), re the following: None. Funding/Support nd role of the sponsor: None. References [1] Ljungerg B, Cown NC, Hnury DC, et l. EAU guidelines on renl cell crcinom: the updte. Eur Urol ;8: [2] Cmpell SC, Novick AC, Belldegrun A, et l., Prctice Guidelines Committee of the Americn Urologicl Assocition. 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