PSA Recurrence of Prostate Cancer: Published on Cancer Network The Oncology Journal (

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1 PSA Rcunc of Potat Canc: Publihd on Canc Ntwok Th Oncology Jounal Stphn J. Fdland, MD [1] Judd W. Moul, MD [2] John F. Wad, MD [] Oct 1, 21 Choltol Diod [4], [] Volum: 4 Today, bcau of potat-pcific antign PSA cning, potat canc in mot patint i dtctd ali and at young ag than in th pat. Dpit thi aly dtction and aft dfinitiv thapy, whth by adical potatctomy RP o adiation thapy RT, a biochmical cunc will dvlop within 1 ya of tatmnt in about % of mn.1,2 With about 2, ca of potat canc diagnod ach ya in th Unitd Stat, it i timatd that a PSA-only cunc dvlop in mo than, mn p ya. Although th natual hitoy of PSA cunc can b long,4 cnt tudi hav hlpd u tatify mn fo vaying ik of clinical pogion and potat canc dath with v-incaing accuacy.4-7 In thi viw, w dicu PSA cunc aft pimay thapy. W focu on th dfinition of cunc, th natual hitoy and ik facto fo pogion, th ol of alvag thapi aimd at cu o palliation, and th timing of th thapi. W alo off advic on how to incopoat thi infomation into clinical pactic. PSA RECURRENCE DEFINED Duing RP, ntially all PSA-poducing cll hould hav bn movd. Thfo, light lvation in PSA lvl a ud to indicat canc cunc. Th xact lvl that dfin PSA cunc i dbatd, howv. In gnal, a PSA lvl high than.4 o.2 ng/ml ha bn ud in mot tudi., PSA lvl do not fall to undtctabl lvl aft RT a thy do aft RP. Rath, adiation induc a low and not alway tady dclin in PSA lvl. Th mdian tim to PSA nadi i about 1 month--and poibly long following bachythapy. In addition, light tanint upwing in PSA lvl PSA bounc a not uncommon. Thfo, dfining cunc in thi tting i mo challnging. In 17, th Amican Socity fo Thaputic Radiology and Oncology ASTRO convnd a connu panl who mmb dfind cunc aft RT a concutiv lvatd PSA valu aft aching a nadi, o a ingl lvatd valu ignificant nough to tigg th initiation of homon thapy.1 Th failu dat i backdatd to th midpoint btwn PSA nadi and th fit of th lvatd PSA valu. Thi backdating intoduc a bia that ovtimat th ucc at hot follow-up tim not nough follow-up ha occud to documnt failu. Moov, in long-tm follow-up tudi, th failu a backdatd to an ali point in tim, ulting in a lvling of th Kaplan-Mi cuv, in contat to outcom aft RP in which PSA-f uvival continu to dclin ov tim.11 Bcau of th concn mntiond abov, ASTRO cntly convnd a nw connu panl that dfind cunc: a PSA valu high than abolut nadi plu 2 ng/ml o a PSA valu high than abolut nadi plu ng/ml.12 Both dfin th failu dat a that whn cunc wa mt i, failu tim i no long backdatd. NATURAL HISTORY OF PSA RECURRENCE Pag 1 of 12

2 PSA Rcunc of Potat Canc: Publihd on Canc Ntwok Th Oncology Jounal Th natual hitoy of PSA cunc can b quit long but vai. In a claic tudy at John Hopkin Univity, Pound and aociat4 dcibd 1 mn with PSA failu following RP who did not civ homonal thapy until th tim of mtatai. Th mdian tim fom PSA cunc to mtatai wa ya, and th mdian tim fom mtatai to dath wa ya. In a cnt follow-up tudy fom John Hopkin that includd a lightly lag cohot, th mdian tim fom PSA cunc to potat canc dath wa not achd aft 1 ya of follow-up. Howv, potat canc dath w n a aly a 1 ya aft PSA cunc, although with vy a fquncy. Thu, th natual hitoy of cunt potat canc i on of a lowly poging dia, but in om mn th pogion can b quit apid. RISK FACTORS FOR CLINICAL PROGRESSION AND PROSTATE CANCER DEATH Givn thi long but vaiabl natual hitoy, many invtigato ought to idntify ik facto to pdict th liklihood of clinical pogion and potat canc dath. Th vaiabl that ha mot conitntly bn linkd with adv outcom i how fat th um PSA lvl i iing, which i mot commonly maud a PSA doubling tim PSADT. Naly 1 ya ago, Cat and collagu1 fit dmontatd that chang in PSA lvl ov tim could pdict th liklihood of potat canc. Shotly thaft, PSA kintic w hown to pdict th ik of ditant vu local failu among mn with PSA failu aft RT14 and aft RP.1 Th initial obvation w confimd in lat tudi.4,7,1-1 A apid PSADT ha bn linkd not only to ik of mtatai but alo to potat canc dath.-7,2 Th aociation btwn PSADT and potat canc dath i o tong that D'Amico and cowok,21 in a tudy of mn who civd both RT and RP, uggtd that a PSADT of l than month could b ud a a uogat nd point fo potat canc dath. Figu On iu ha ain whn xamining PSADT: What i th optimal cut point to paat high-ik fom low-ik cunc? Vaiou cut point hav bn dcibd at,,21,22,2 1,4 and 1221 month. Givn th multipl cut point, it i likly that th aociation btwn PSADT and ik of cunc i on a continuum. D'Amico and collagu,21 in thi analyi of RP and RT patint, found that among mn with a PSADT of mo than month, PSADT a a continuou vaiabl wa ignificantly aociatd with ik of potat canc dath. Mot cntly, thi continuum btwn PSADT and ik wa hown by Fdland and cowok; multipl cut point w idntifid that tatifid mn into 4 ik goup Tabl 1, Figu. Tabl 1 Etimatd 1-ya ik of potat canc pcific uvival aft biochmical cunc following adical potatctomy Rik timat, % % CI Rcu nc R Pag 2 of 12

3 PSA Rcunc of Potat Canc: Publihd on Canc Ntwok Th Oncology Jounal ya aft ugy c u n c > y a a ft u g y PSADT month Glaon co G l a o n c o < G l a o n c o G l a o n c o < <. 1 < Pag of 12

4 PSA Rcunc of Potat Canc: Publihd on Canc Ntwok Th Oncology Jounal CI, confidnc intval; PSADT, potat-pcific antign doubling tim. Adaptd with pmiion fom Fdland SJ t al. JAMA. 2. Oth vaiabl hav bn xamind fo thi aociation with mtatai and potat canc dath, although whth thy add infomation to PSADT i dbatabl. Fo xampl, om24,2 but not all,22,2 tudi found that pathologic Glaon um pdictd tim to mtatai o potat canc dath. Similaly, contovy xit gading th pognotic valu of tim to PSA cunc: mot22,2,27 but not all7 tudi found it wa an impotant pdicto of outcom. Although th abolut PSA valu i gnally not pdictiv of tim to mtatai o tim to potat canc dath aft adjuting fo PSADT, it i pdictiv of th liklihood of a bon can bing poitiv.1,17 SALVAGE RADIOTHERAPY Th pon at to alvag RT hav bn modt, with ult vaying gatly aco tudi.24,2-4 In on of th lagt tudi to dat, which poold data fom multipl intitution, th PSA-f pogion at at 4 ya aft alvag RT wa 4%. Givn thi modt ucc, invtigato hav ought to idntify ik facto fo a favoabl outcom aft alvag RT. Th vaiabl that ha conitntly bn linkd with th ucc of alvag RT i th PSA valu at th tim of RT. In gnal, th low th PSA valu, th btt th outcom, although th bt cutoff to dfin "low" PSA valu ha vaid among tudi anging fom l than. ng/ml to l than 2.1 ng/ml. Oth vaiabl that hav bn colatd with uccful alvag RT includ th adiation do Pag 4 of 12

5 PSA Rcunc of Potat Canc: Publihd on Canc Ntwok Th Oncology Jounal givn,7,,4 th Glaon co,2,,, poitiv ugical magin,4, xtacapula xtnion,4 lack of minal vicl invaion,1,,, and th p-rt PSADT.2,, Howv, many of th tudi includd only a mall numb of mn, limiting th ability to dtct impotant obvation about pdicto of alvag RT ucc. It i likly that thi limitation, ath than tu biologic diffnc btwn tudy population, account fo diffnc in ult among th vaiou i. Dpit th cnt publication, th ultimat impact of alvag RT on uvival i till unknown. Mot patint, including tho with multipl adv indicato, appa to achiv at lat an initial pon. Although th duability of thi pon i hot-livd fo mot patint, it i till poibl th RT ha hiftd th biologic bhavio of th canc. Whth thi i fo btt o wo qui mo invtigation. SALVAGE RADICAL PROSTATECTOMY Hitoically, alvag RP wa not pfomd bcau of concn about ffctivn and anxity about opating on adiatd tiu, which would mak ugy mo difficult and could ult in unaccptabl mobidity. Howv, contmpoay tudi of mn who hav undgon alvag RP, who w lctd bad on a iing um PSA lvl ath than on a ymptomatic cunc, hav mo accptabl at of mobidity and ignificant impovmnt in both local and ditant canc contol at In 2 of th lagt tudi to dat, th 1-ya potat canc-pcific uvival at aft alvag RP wa % to 7%.41,44 Among cafully lctd patint, th complication at can appoach tho n with pimay RP, and quality-of-lif outcom a only modtly wo than tho of pimay RP patint.4 Evn in contmpoay tudi, up to 2% of patint qui a cytopotatctomy fo adquat tumo xciion,41 which i nough to dicouag mot uologit fom attmpting alvag RP. Salvag RP may off om patint both local and ditant dia contol with a aonabl id ffct pofil, but it i till not commonly ud in clinical pactic. SALVAGE CRYOTHERAPY Anoth altnativ fo mn with a cunc aft RT i alvag cyothapy. With th advnt of thid-gnation cyothapy quipmnt uing agon ga, mall cyopob, and a "bachythapy-lik" appoach, intt in alvag cyothapy i on th i. Han and aociat4 potd initial ult of a multicnt tial of th u of thid-gnation cyothapy. No majo complication w notd with thi thapy, a oppod to pviou cyothapy whn ctal fitu- la w a majo poblm. Simila to oth pot of contmpoay al-vag cyothapy,47 impotnc wa naly unival and th incidnc of oth id ffct, uch a incontinnc, wa low l than 1%. Follow-up wa vy limitd; 77% of alvag patint had a PSA valu low than.4 ng/ml at 12 month. Long-tm follow-up i ndd to a th impact of alvag cyothapy on canc contol. HORMONAL THERAPY Homonal dpivation thapy ha bn th mot avidly ud tatmnt fo advancd potat canc inc it dciption by Huggin and Hodg4 in 141--a dicovy fo which D Huggin had th Nobl Piz in mdicin in 1. Howv, unlik th alvag thapi mntiond abov, homonal thapy i not cuativ; with long-tm follow-up, homon itanc will dvlop in naly all mn. Th tm "homonal thapy" f to tatmnt aimd at ith liminating ttoton poduction ugical o phamacologic catation; pvnting th binding of ttoton to cllula cpto toidal o nontoidal antiandogn; o a combination of both, known a complt andogn blockad CAB. In addition, th ha bn a gowing intt in intmittnt homonal thapy.4 Whil homonal thapy can ult in damatic tumo hinkag and off tmndou lif of Pag of 12

6 PSA Rcunc of Potat Canc: Publihd on Canc Ntwok Th Oncology Jounal ymptom fo mn who hav mtatatic dia, it ol in ali-tag dia i, nonmtatatic PSA cunc i contovial. Fw oth topic in potat canc managmnt gnat a much hatd dbat. Th aon fo th dbat tm fom th fact that homonal thapy i not bnign. Th ngativ impact on quality of lif can b ignificant: hot flah, bon lo, incad ik of factu, xual dyfunction, lo of libido, mmoy lo, incad fat dpoition, lo of mucl ma, and incad choltol lvl and oth mtabolic chang that may inca th ik of hat dia.,1 Oth ngativ includ cot and poibl dug action. Howv, in th wll-lctd patint, th poibl bnfit of dlayd mtatai, ducd kltal mobidity fom mtatai, and polongd uvival may outwigh th ik and jutify u of homonal thapy. Unfotunatly, th a limitd data on th ol of homonal thapy fo mn with PSA-only cunc and nonmtatatic dia. Thfo, w a lft to xtapolat data fom tial ith of mn with mtatatic dia o of tho with locally advancd nonmtatatic dia. Howv, whth uch data can b applid to mn with PSA-only cunc i till a matt of dbat. Blow w dicu val tudi on th ol of homonal thapy fo potat canc in gnal, which may o may not b applicabl to mn with PSA-only cunc. On qution that ha civd a lot of attntion i whth CAB i mo fficaciou than mdical/ugical catation alon. CAB i mo cotly and ha an incad id ffct pofil compad with catation alon.2 Sid ffct includ liv toxicity mo common with flutamid and bat nlagmnt/tndn mo common with bicalutamid.2 I it mo fficaciou? Many tudi hav addd thi pcific point with mixd ult, thu poviding ampl tudi to uppot ith opinion. Although om invtigato claim that CAB can cu % of patint, mta-analy how th bnfit of CAB to duc th ik of potat canc dath appa to b modt, anging fom a nonignificant duction of 7%4, to ignificant duction of 1% to 2%.7 Th modt ult, combind with cot and adv ffct on quality of lif,2 hav tmpd nthuiam fo CAB among om phyician. Mot of th tudi, howv, w pfomd bfo th impotanc of PSADT in ik tatification wa undtood. It i poibl that though ik tatification, w can idntify mn who tand to bnfit mot fom CAB and tho who tand to bnfit lat and may actually b hamd by it o by any homonal thapy. EARLY VERSUS DELAYED HORMONAL THERAPY Th timing of homonal thapy i an xtmly contovial topic that ha bn xamind and xamind fo dcad. Th i till no connu, although phap th cal a tipping towad aly homonal thapy--at lat fo om mn. In th 1 and 17, th Vtan Adminitation Coopativ Uological Rach Goup compad aly with dfd homonal thapy ith ochictomy o togn and found no diffnc in ovall uvival. Howv, th patint in that tudy had much mo advancd dia than typical patint today with PSA-only cunt dia. Th u of togn, with it aociatd cadiovacula mobidity, uggt that th ult may not apply to patint today. Th Mdical Rach Council in th Unitd Kingdom compad immdiat mdical o ugical catation with dfd tatmnt among naly 1 patint who had locally advancd o aymptomatic mtata-tic dia. Initial ult dmontatd that aly thapy dlayd dia pogion, dlayd th ont of nw mtatatic pain, and ignificantly ducd potat canc and ovall dath. Whil long follow-up confimd th advantag of immdiat homonal thapy on impovd dia-pcific uvival, th wa no long any diffnc in ovall uvival, flcting incad motality fom oth cau. Thi tudy wa citicizd bcau om mn in th dlayd am nv civd homonal thapy, potntially biaing th ult in favo of aly thapy.1 Howv, th diffnc in finding btwn th initial and long-tm ult a intiguing: with limitd follow-up uch that only tho mot likly to di of potat canc a at ik, aly homonal thapy wa btt; with long Pag of 12

7 PSA Rcunc of Potat Canc: Publihd on Canc Ntwok Th Oncology Jounal follow-up uch that all mn a at ik, no ovall bnfit wa n. Thi tongly uggt that aly homonal thapy may b btt fo om mn i, tho at hight ik but may hav no bnfit o may poibly ham oth i, tho at lowt ik. In a andomizd tudy of aly vu dlayd homonal thapy among mn with micocopic nodal involvmnt at th tim of RP, th Eatn Coopativ Oncology Goup potd a ignificant ducd all-cau and potat canc-pcific motality favoing aly tatmnt.2 In mn who civd immdiat homonal thapy, th motality at fom potat canc at 7-ya follow-up wa 4.%, compad with a motality at of.% in mn who w initially obvd P <.1. Futhmo, th cunc at w 1.% vu 7% favoing immdiat tatmnt. Whth thi tudy can b xtapolatd to jutify a bnfit fo aly homonal thapy fo mn with PSA-only cunc i unknown. Tabl 2 Multivaiabl Cox popotional hazad analyi of lat homonal thapy pdicting tim to mtatai among mn with PSA cunc following adical potatctomy in th Cnt fo Potat Dia Rach Databa Lat* v aly homonal thapy Hazad atio P v a l u All patint >. PSA cunc within 1 ya aft ugy Pag 7 of 12

8 PSA Rcunc of Potat Canc: Publihd on Canc Ntwok Th Oncology Jounal Pathologic Glaon co > 7 o PSADT 12 month PSA, potat-pcific antign; CI, confidnc intval; PSADT, PSA doubling tim. *Lat homonal thapy dfind a non o bgun with a PSA > ng/ml. Ealy homonal thapy dfind a bgun whn PSA ng/ml. Adaptd with pmiion fom Moul JW t al. J Uol. 24. To dat, only on topctiv tudy xamind th iu of th timing of homonal thapy. Moul and collagu potd a i of 12 mn with biochmical cunc following RP. Th invtigato found that aft a mdian follow-up of.7 ya aft cunc, aly homonal thapy had no ffct on tim to mtatai among th ovall cohot Tabl 2. Th limitd follow-up pvntd maningful analyi of potat canc dath. Among mn with high-ik dia pathologic Glaon um mo than 7 o a PSADT of 12 month o l, aly homonal thapy tating whn th PSA valu w l than o l than 1 ng/ml wa aociatd with a % duction in th ik of mtatai. Whil no popctiv andomizd contolld tial hav pcifically addd th timing of homonal thapy in mn with PSA-only cunc, th i mounting vidnc uggting a bnfit to aly thapy in patint with high-ik dia. Howv, th id ffct of taditional homonal thapy mut not b undtimatd, paticulaly in mn who a clinically wll with only a iing um PSA lvl. Futhmo, what xactly dfin "aly" thapy i till uncla, bcau all pntd tudi initiatd tatmnt at diffnt dia tag. NONTRADITIONAL HORMONAL THERAPIES Whil mdical and ugical catation can hav a damatic ffct on potat canc, a notd abov, thy cay ignificant quality-of-lif concn. Thfo, th i a cla nd fo ffctiv but l toxic thapi. On uch option i antiandogn alon. Th mot xtnivly valuatd dug i bicalutamid. An ovviw analyi of opn, andomizd, multicnt tudi compaing bicalutamid with ugical o mdical catation found that bicalutamid mg/d wa l ffctiv than catation with pct to tim-to-tatmnt failu, tim-to-objctiv pogion, uvival, and ubjctiv pon at.4 Standad-do bicalutamid appa l fficaciou than catation, but high-do bicalutamid 1 mg/d ha bn hown to povid a uvival outcom imila to that of catation fo mn with locally advancd nonmtatatic dia. In addition, in thi tudy, quality of lif fo patint who civd high-do bicalutamid appad to b imila o lightly btt than quality of lif fo tho who had undgon catation. Th ult fom th Ealy Potat Canc Pogam that compad high-do bicalutamid with placbo w potd. Thi tudy compid andomizd, doubl-blind, placbo-contolld tial of imila dign aco ditinct gogaphic aa. Mn n = 11 with potat canc undgoing RP, RT, o watchful waiting w andomizd to civ adjuvant high-do bicalutamid o placbo fo ya Noth Amica o ya Autalia, Euop, Ial, South Afica, Mxico, and Scandinavia. Th pimay nd point wa pogion-f uvival and ovall uvival. Tolability Pag of 12

9 PSA Rcunc of Potat Canc: Publihd on Canc Ntwok Th Oncology Jounal wa a conday nd point. Mdian follow-up aft andomization wa.4 ya. Whn data fom th tudi w xamind paatly o combind, no ignificant diffnc in ovall uvival btwn th bicalutamid and placbo goup wa obvd. Whn th data w tatifid by dfinitiv tatmnt vu watchful waiting and tag of dia local vu locally advancd, a vy intting obvation wa notd: among mn who civd RP o RT, bicalutamid wa not ignificantly latd to ovall uvival gadl of dia tag. Whn data fom mn who w managd with watchful waiting w xamind, bicalutamid wa aociatd with an impovmnt in ovall uvival, which did not ach tatitical ignificanc hazad atio [HR],.1; % confidnc intval [CI],. to 1.4; P =.1 among mn with advancd dia, but ignificantly wo ovall non-canc-pcific uvival among mn with localizd dia HR, 1.2; % CI, 1. to 1.; P =.. Thu, mn with advancd dia who w managd with watchful waiting w 1% l likly to di whil civing bicalutamid, wha mn with localizd dia who w managd with watchful waiting w 2% mo likly to di whil taking bicalutamid. Th data cho ult fom pviou tudi: tho at th hight ik likly gain a ignificant advantag with aggiv aly homonal thapy, whil tho at lowt ik a likly hamd by th am tatmnt. An impotant clinical not latd to high-do bicalutamid i that bat nlagmnt and tndn occu in up to 7% of patint. A andomizd tial howd that pophylactic bat iadiation o tamoxifn 1 mg daily could pvnt th bat pain, with tamoxifn bing lightly mo ffctiv than bat iadiation.7 Rfnc: REFERENCES: 1. Han M, Patin AW, Pound CR, t al. Long-tm biochmical dia-f and canc-pcific uvival following anatomic adical topubic potatctomy. Th 1-ya John Hopkin xpinc. Uol Clin Noth Am. 21;2:-. 2. Djavan B, Moul JW, Zlotta A, t al. PSA pogion following adical potatctomy and adiation thapy: nw tandad in th nw millnnium. Eu Uol. 2;4: Moul JW. Potat pcific antign only pogion of potat canc. J Uol. 2;1: Pound CR, Patin AW, Einbg MA, t al. Natual hitoy of pogion aft PSA lvation following adical potatctomy. JAMA. 1;21: D'Amico AV, Moul JW, Caoll PR, t al. Suogat nd point fo potat canc-pcific motality aft adical potatctomy o adiation thapy. J Natl Canc Int. 2;: Fdland SJ, Humphy EB, Mangold LA, t al. Rik of potat canc-pcific motality following biochmical cunc aft adical potatctomy. JAMA. 2;24: Wad JF, Blut ML, Slzak J, t al. Th long-tm clinical impact of biochmical cunc of potat canc o mo ya aft adical potatctomy. J Uol. 2;17: Amling CL, Bgtalh EJ, Blut ML, t al. Dfining potat pcific antign pogion aft adical potatctomy: what i th mot appopiat cut point? J Uol. 21;1: Fdland SJ, Sutt ME, Doy F, Aonon WJ. Dfining th idal cutpoint fo dtmining PSA cunc aft adical potatctomy. Potat-pcific antign. Uology. 2;1:-. 1. Howitz EM, Vicini FA, Ziaja EL, t al. Th colation btwn th ASTRO Connu Panl dfinition of biochmical failu and clinical outcom fo patint with potat canc tatd with xtnal bam iadiation. Amican Socity of Thaputic Radiology and Oncology. Int J Radiat Oncol Biol Phy. 1;41: Amling CL, Blut ML, Bgtalh EJ, t al. Long-tm hazad of pogion aft adical potatctomy fo clinically localizd potat canc: continud ik of biochmical failu aft ya. J Uol. 2; 14: Howitz EM, Tham HD, Kuban DA, t al. Dfinition of biochmical failu that bt pdict clinical failu in patint with potat canc tatd with xtnal bam adiation alon: a multi-intitutional poold analyi. J Uol. 2;17: Cat HB, Paon JD, Mtt EJ, t al. Longitudinal valuation of potat-pcific antign lvl in mn with and without potat dia. JAMA. 12;27: Zaga GK, Pollack A. Th fall and i of potat-pcific antign. Kintic of um potat-pcific antign lvl aft adiation thapy fo potat canc. Canc. Pag of 12

10 PSA Rcunc of Potat Canc: Publihd on Canc Ntwok Th Oncology Jounal 1;72: Tapao JG, dknion JB, Smith RB, Doy F. Th incidnc and ignificanc of dtctabl lvl of um potat pcific antign aft adical potatctomy. J Uol. 14;12: Okoti OT, Aonon WJ, Wid JA, t al. Pdicto of mtatatic dia in mn with biochmical failu following adical potatctomy. J Uol. 24;171: Kan CJ, Amling CL, Johnton PA, t al. Limitd valu of bon cintigaphy and computd tomogaphy in aing biochmical failu aft adical potatctomy. Uology. 2;1: Sato CI, Stawdman MH, Lin XH, t al. Rat of PSA i pdict mtatatic vu local cunc aft dfinitiv adiothapy. Int J Radiat Oncol Biol Phy. 17;: Patin AW, Paon JD, Landi PK, t al. Evaluation of um potat-pcific antign vlocity aft adical potatctomy to ditinguih local cunc fom ditant mtata. Uology. 14;4: Albtn PC, Hanly JA, Pnon DF, Fin J. Validation of incaing potat pcific antign a a pdicto of potat canc dath aft tatmnt of localizd potat canc with ugy o adiation. J Uol. 24;171: D'Amico AV, Cot K, Loffdo M, t al. Dtminant of potat canc-pcific uvival aft adiation thapy fo patint with clinically localizd potat canc. J Clin Oncol. 22;2: Patl A, Doy F, Fanklin J, dknion JB. Rcunc pattn aft adical topubic potatctomy: clinical ufuln of potat pcific antign doubling tim and log lop potat pcific antign. J Uol. 17;1: Zaga GK, Pollack A. Kintic of um potat-pcific antign aft xtnal bam adiation fo clinically localizd potat canc. Radioth Oncol. 17;44: Kim-Sing C, Pickl T; Potat Cohot Outcom Initiativ. Intvntion aft PSA failu: xamination of intvntion tim and ubqunt outcom fom a popctiv patint databa. Int J Radiat Oncol Biol Phy. 24;: Pinov WH, Howitz EM, Hanlon AL, t al. Validation of a tatmnt policy fo patint with potat pcific antign failu aft th-dimnional confomal potat adiation thapy. Canc. 2;7: Robt SG, Blut ML, Bgtalh EJ, t al. PSA doubling tim a a pdicto of clinical pogion aft biochmical failu following adical potatctomy fo potat canc. Mayo Clin Poc. 21;7: Hanlon AL, Diatzouian H, Hank GE. Pottatmnt potat-pcific antign nadi highly pdictiv of ditant failu and dath fom potat canc. Int J Radiat Oncol Biol Phy. 22;: Lvnti AK, Shaiat SF, Kattan MW, t al. Pdiction of pon to alvag adiation thapy in patint with potat canc cunc aft adical potatctomy [publihd coction appa in J Clin Oncol. 21;1:21]. J Clin Oncol. 21;1: Chawla AK, Thakal HK, Zitman AL, Shiply WU. Salvag adiothapy aft adical potatctomy fo potat adnocacinoma: analyi of fficacy and pognotic facto. Uology. 22;: Cadddu JA, Patin AW, DW TL, Walh PC. Long-tm ult of adiation thapy fo potat canc cunc following adical potatctomy. J Uol. 1;1: Koppi TM, Gofld GD, Nudll DM, t al. I anatomotic biopy ncay bfo adiothapy aft adical potatctomy? J Uol. 21;1: Nudll DM, Gofld GD, Winbg VK, t al. Radiothapy aft adical potatctomy: tatmnt outcom and failu pattn. Uology. 1;4: Liauw SL, Wbt WS, Pitnmaa DA, Rohbon CG. Salvag adiothapy fo biochmical failu of adical potatctomy: a ingl-intitution xpinc. Uology. 2;1: Katz MS, Zlfky MJ, Vnkataman ES, t al. Pdicto of biochmical outcom with alvag confomal adiothapy aft adical potatctomy fo potat canc. J Clin Oncol. 2;21:4-4.. Stphnon AJ, Shaiat SF, Zlfky MJ, t al. Salvag adiothapy fo cunt potat canc aft adical potatctomy. JAMA. 24;21: Vanuytl L, Jann G, Van Poppl H, t al. Radiothapy fo PSA cunc aft adical potatctomy. Eu Uol. 21;: Anch MS, Clough R, Dodg R. Radiothapy fo a iing potat-pcific antign aft adical potatctomy: th fit 1 ya. Int J Radiat Oncol Biol Phy. 2;4:-7.. Wad JF, Zinck H, Bgtalh EJ, t al. Potat pcific antign doubling tim ubqunt to Pag 1 of 12

11 PSA Rcunc of Potat Canc: Publihd on Canc Ntwok Th Oncology Jounal adical potatctomy a a pognoticato of outcom following alvag adiothapy. J Uol. 24;172: MacDonald OK, Schild SE, Voa S, t al. Salvag adiothapy fo mn with iolatd iing PSA o locally palpabl cunc aft adical potatctomy: do outcom diff? Uology. 24;4: Cox JD, Gallagh MJ, Hammond EH, t al. Connu tatmnt on adiation thapy of potat canc: guidlin fo potat -biopy aft adiation and fo adiation thapy with iing potat-pcific antign lvl aft adical potatctomy. Amican Socity fo Thaputic Radiology and Oncology Connu Panl. J Clin Oncol. 1;17: Wad JF, Sbo TJ, Blut ML, Zinck H. Salvag ugy fo adiocunt potat canc: contmpoay outcom. J Uol. 2;17: Ghil EL, Tfilli MV, Tigut R, t al. Pdicto fo maximal outcom in patint undgoing alvag ugy fo adio-cunt potat canc. Uology. 1;1: Gazotto M, Wajman Z. Andogn dpivation with alvag ugy fo adiocunt potat canc: ult at -ya followup. J Uol. 1;1: Bianco FJ J, Scadino PT, Stphnon AJ, t al. Long-tm oncologic ult of alvag adical potatctomy fo locally cunt potat canc aft adiothapy. Int J Radiat Oncol Biol Phy. 2;2: Stphnon AJ, Scadino PT, Bianco FJ J, t al. Mobidity and functional outcom of alvag adical potatctomy fo locally cunt potat canc aft adiation thapy. J Uol. 24;172: Han KR, Cohn JK, Mill RJ, t al. Tatmnt of ogan confind potat canc with thid gnation cyougy: pliminay multicnt xpinc. J Uol. 2;17: Anataiadi AG, Sachdv R, Salomon L, t al. Compaion of halth-latd quality of lif and potat-aociatd ymptom aft pimay and alvag cyothapy fo potat canc. J Canc R Clin Oncol. 2;12: Huggin C, Hodg CV. Studi on potatic canc, I: th ffct of catation, of togn and of andogn injction on um phophata in mtatatic cacinoma of th potat J Uol. 22;1: Bhandai MS, Cook J, Huain M. Should intmittnt andogn dpivation b ud in outin clinical pactic? J Clin Oncol. 2;2: Pnon DF, Litwin MS. Th phyical budn of potat canc. Uol Clin Noth Am. 2;: Shaifi N, Gully JL, Dahut WL. Andogn dpivation thapy fo potat canc. JAMA. 2; 24: Bayoumi AM, Bown AD, Gab AM. Cot- ffctivn of andogn uppion thapi in advancd potat canc. J Natl Canc Int. 2; 2: Labi F, Blang A, Luu-Th V, t al. Gonadotopin-laing homon agonit in th tatmnt of potat canc. Endoc Rv. 2;2: Maximum andogn blockad in advancd potat canc: an ovviw of 22 andomid tial with 2 dath in 71 patint. Potat Canc Tialit' Collaboativ Goup. Lanct. 1;4: Maximum andogn blockad in advancd potat canc: an ovviw of th andomid tial. Potat Canc Tialit' Collaboativ Goup. Lanct. 2;: Samon DJ, Sidnfld J, Schmitt B, t al. Sytmatic viw and mta-analyi of monothapy compad with combind andogn blockad fo patint with advancd potat cacinoma. Canc. 22;: Klotz L, Schllhamm P. Combind andogn blockad: th ca fo bicalutamid. Clin Potat Canc. 2;: Bya DP, Col DK. Homon thapy fo potat canc: ult of th Vtan Adminitation Coopativ Uological Rach Goup tudi. NCI Monog. 1;7: Immdiat vu dfd tatmnt fo advancd potatic canc: initial ult of th Mdical Rach Council Tial. Th Mdical Rach Council Potat Canc Woking Paty Invtigato Goup. B J Uol. 17;7: Kik D. Immdiat v dfd homon tatmnt fo potat canc: how af i andogn dpivation? B J Uol. 2;uppl :S Walh PC. Immdiat vu dfd tatmnt fo advancd potatic canc: initial ult of th Mdical Rach Council tial. Th Mdical Rach Council Potat Canc Woking Paty Invtigato Goup. J Uol. 17;1: Pag 11 of 12

12 PSA Rcunc of Potat Canc: Publihd on Canc Ntwok Th Oncology Jounal 2. Ming EM, Manola J, Saody M, t al. Immdiat homonal thapy compad with obvation aft adical potatctomy and plvic lymphadnctomy in mn with nod-poitiv potat canc. N Engl J Md. 1;41: Moul JW, Wu H, Sun L, t al. Ealy vu dlayd homonal thapy fo potat pcific antign only cunc of potat canc aft adical potatctomy. J Uol. 24;171: Bal GT, Chodak GW. A contolld tial of bicalutamid vu catation in patint with advancd potat canc. Uology. 1;47uppl 1A: -4.. Ivn P, Tyll CJ, Kaiay AV, t al. Bicalutamid monothapy compad with catation in patint with nonmtatatic locally advancd potat canc:. ya of followup. J Uol. 2;14: With MP, S WA, McLod DG, t al; Caodx Ealy Potat Canc Tialit' Goup. Bicalutamid 1 mg in addition to tandad ca in patint with localizd o locally advancd potat canc: ult fom th cond analyi of th aly potat canc pogam at mdian followup of.4 ya. J Uol. 24;172: Di Lonzo G, Pdona S, D Placido S, t al. Gyncomatia and bat pain inducd by adjuvant thapy with bicalutamid aft adical potatctomy in patint with potat canc: th ol of tamoxifn and adiothapy. J Uol. 2;174: Souc URL: Link: [1] [2] [] [4] [] Pag 12 of 12