Jurnal Adjuvan Pada Kanker Ginjal Stadium 2b

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  • 8/16/2019 Jurnal Adjuvan Pada Kanker Ginjal Stadium 2b


    The prognostic factors,potential

    biomarkers, surgicalstrategies,

    and adjuvant therapy trials for

    patients with locally advanced

    renal cell carcinoma arereviewed.

    Kala Pohl. Let’s Stick Together. Acrylic on canvas, 24 ′′ × 30 ′′ .

    Management of Locally AdvancedRenal Cell Carcinoma

    Alejandro Rodriguez, MD, and Wade J. Sexton, MD

    Background: Renal cell carcinoma accounts for appro imately !" of adult malignancies and over #$" of primary renal tumors. Recurrence rates for patients with locally advanced renal cell carcinoma%L&R''( remain high.Methods: The authors review literature regarding prognostic factors, potential biomarkers,surgical strategies,and adjuvant therapy trials for patients with L&R''.Results: )olecular tumor markers may improve e isting staging systems for predictingprognosis. Surgery isthe best initial treatment for most patients with clinically locali*ed renal tumors, althoughcomplete surgicalresection can be challenging for patients with large tumors, bulky regional lymph nodeinvolvement, or inferior vena cava tumor thrombus. Signi+cant recurrence rates for patients with L&R'' undergoingnephrectomy indicatethe presence of undetected micrometastases at the time of surgery. &djuvant radiation,chemotherapy, andimmunotherapy have been ine ective. -ther trials of adjuvant therapy are ongoing.Conclusions: &ggressive surgical resection alone for L&R'' is not su icient to prevent diseaserecurrence in asigni+cant number of patients. &djuvant therapies are needed to improve cancer speci+csurvival.

  • 8/16/2019 Jurnal Adjuvan Pada Kanker Ginjal Stadium 2b


    /rom the 0enitourinary -ncology 1rogram, 2. Lee )o itt'ancer 'enter 3 Research 4nstitute, Tampa, /lorida.

    &ddress correspondence to 5ade 6. Se ton, )7,0enitourinary -ncology 1rogram, 2. Lee )o itt 'ancer 'enter 3 Research 4nsti tute, 89#$9 )agnolia 7rive,Tampa, /L!!:89. ; mail< se tonwj= mo itt.usf.edu

    Submitted )arch 8, 9$$:> accepted )ay 9, 9$$:. ?o signi+cant relationship e ists between the authors andthe com panies@organi*ations whose products or servicesmay be referenced in this article.

    &bbreviations used in this paper< RCC = renal cellcarcinoma, LARCC = locally advanced renal cellcarcinoma, VHL = von Hippel Linda!, H"# $ α = hypo%iaind!ci&le 'ac(or $ alpha, V)*# = vasc!lar endo(helial+ro (h 'ac(or, CA"- = car&onic anhydrase "-, "VC = in'erior vena cava, )C * = )as(ern Coopera(ive ncolo+y*ro!p, "L = in(erle!/in, "# = in(er'eron.


    1!r+ery is (he mos(e icacio!s (herapy'or pa(ien(s i(hnonme(as(a(ic,locali ed renal cellcarcinoma RCC5.Pro+ression 'rees!rvival and overalls!rvival 'ol lo in+nephrec(omy aredependen( on 'ac(orss!ch as pa(holo+ic 6s(a+e, (!mor +rade,lymph node s(a(!s,and per'ormances(a(!s. $,2 Pa(ien(s

    i(h lo s(a+e, lo+rade, and o'(eninciden(ally de(ec(edrenal (!mors have a'avora&le lon+ (ermpro+nosis. $ 3 #or

    pa(ien(s i(hme(as(a(ic disease a(presen(a(ion,nephrec(omy'ollo ed &y sys(emicimm!no(herapyincreases overalls!rvival &y 3 (o $0mon(hs compared

    i(h pa(ien(s

    July 2 006, Vol . 13, No. 3 Cancer Control 199

    (rea(ed i(h imm!no(herapy alone. 4,7 1(ill,i(h m!l(i modali(y (herapy, (he median

    s!rvival 'or pa(ien(s i(h me(as(a(ic diseaseis only $0 (o $2 mon(hs, and 8!s( 29 o' s!chpa(ien(s s!rvive lon+ (erm. : Cen(ered&e( een (hese ( o clinical e%(remes aremany pa(ien(s i(h locally advanced renalcell carcinoma LARCC5 a( ris/ 'orpro+ression and dea(h 'rom (heir renal(!mors d!e (o adverse clinical and pa(holo+ic

    varia&les de(ermined a( (he (ime o'

    presen(a(ion or 'ollo in+ s!r+ery. *iven (healmos( !ni'ormly 'a(al o!(come 'or pa(ien(sho develop me(as(a(ic disease, several

    'ac(ors are para mo!n( (o (he s!ccess'!l(rea(men( o' (hese pa(ien(s; a &e((er!nders(andin+ o' (he varia&les (ha( in

    Characteristics of LARCC

    Diagnosis an d Staging6he preopera(ive assessmen( o' pa(ien(s i(ha renal lesion has (hree principal aims; (oma/e (he dia+nosis o' RCC, (o assess (hes(a+e o' disease, and (o delinea(e (heana(omic de(ail necessary 'or opera(iveplannin+. Pa(ien(s i(h LARCC can presen(

    i(h a myriad o' si+ns and symp(omsa((ri&!(a&le (o (he primary (!mor (o incl!de(he classic (riad o'

  • 8/16/2019 Jurnal Adjuvan Pada Kanker Ginjal Stadium 2b


    radiolo+ic assessmen( o' (he e%(en( o' local ordis(an( disease. "ma+in+ o' (he ches(,

    Table 1. — Classication of RCC and Frequency of Histologic S ubtypes

    Malignant Neoplasms Frequency (%)Clear cell RCC 70–80Papillary R CC 15Chromophobe RCC 5Collecting duct car cinoma < 1

    RCC unclassied < 5

    a&domen, and pelvis sho!ld &e per'ormedi(h com p!(ed (omo+raphy C65 or a

    com&ina(ion o' C6, ma+ ne(ic resonanceima+in+,or s(andard ches( radio+raphy.La&ora(ory &iochemical eval!a(ion incl!des aro!(ine comple(e &lood co!n( and a comple(eme(a&olic panel speciBcally eval!a(in+ (heser!m crea(inine, &lood !rea ni(ro+en, liver'!nc(ion (es(s, ser!m calci!m, and al/a linephospha(ase. "' (he pa(ien( complains o' a(ypical m!sc!los/ele(al discom'or( or i' (he&iochemical s(!d ies indica(e possi&le &oneme(as(ases, a &one scan sho!ld &econsidered. Presen(ly, posi(ron emission(omo+raphy is no( considered par( o' (hes(a+in+ or/!p 'or (he ne ly dia+nosed renalmass hen o(her dia+nos(ic s(!dies reveal noevidence 'or sys (emic disease. 6he advancesin ima+in+ (echnolo+y have drama(icallyenhanced (he vis!ali a(ion o' ana(omic de(ail,especially vasc!lar ana(omy. 1!ch de(ail iscr!cial 'or nephron sparin+ cases and in

    si(!a (ions o' veno!s (!mor (hrom&!s. "nmany s!ch ins(ances, (he need 'or invasiveima+in+ i(h ar(erio+ raphy or veno+raphyhas &een o&via(ed &y (he recon s(r!c(ivecapa&ili(y o' modern cross sec(ional ima+in+.

    Pathologic Characteristics and Potential

    Markers o f Advanced Disease

    6he orld Heal(h r+ani a(ion moderni ed(he classiB ca(ion o' renal (!mors 6a&le $5.

    Al(ho!+h clear cell RCCs acco!n( 'or ?09 o'

    primary mali+nan( renal (!mors, @09 o' (!mors (ha( me(as(asi e come 'rom (heconven(ional clear cell carcinoma, i(h $09ori+ina(in+ 'rom o(her his(olo+ic s!&(ypesincl!din+ papillary and chromopho&ecarcinomas. $3 1everal pa(holo+ic 'ea(!resincl!din+ primary (!mor +rade, (!mor si e,pa(holo+ic 6 s(a+e, his(olo+ic (!mor necrosis,and lymph node s(a(!s are all ell accep(ed,independen( pro+nos(ic 'ac(ors 'or predic(in+pro+ression 'ree and overall s!r vival 6a&le25.$,2,$4 6he #!hrman sys(em is (he mos(common his(olo+ic /idney cancer +radin+

  • 8/16/2019 Jurnal Adjuvan Pada Kanker Ginjal Stadium 2b


    sys(em in or(h America. *rade " elldi eren(ia(ed5 (o +rade "V poorlydi eren(ia(ed5 pa((erns are assi+ned &asedon n!clear and n!cleolar si e, shape, andcon(en(. $7 1arcoma(oid (!mors are no lon+erconsidered a dis(inc( his(olo+ic s!&(ype o'

    RCC. 6hey are !ncommon oc c!rrin+ in less(han 79 o' RCCs5, hi+h +rade, a++ressive'orms o' RCC i(h spindle cell pa((erns o' di eren(ia (ion and are associa(ed i(h apoor pro+nosis. $: hile i( is di ic!l( (ode(ermine (he '!ll impac( o' each inde

    200 Cancer Control July 2 006, Vol. 13, No. 3

    penden( varia&le alone on pro+ression ands!rvival par(ic!larly 'or conven(ional clearcell his(olo+y5, (he pro+nos(ic si+niBcance o' each varia&le &ecomes m!ch more po er'!l

    hen incorpora(ed in(o m!l(ivaria(e modelso' s!rvival. $,2,$4 #ive year ra(es o' pro+ression 'ree s!rvival and overall s!rvivalran+e 'rom $39 (o @@9 and 209 (o @$9,respec(ively incl!din+ D E0 cases5,dependin+ on (he presence and com&ina(iono' (hese varia&les. $,2

    6he na(!ral his(ory o' sporadic RCCscanno( al ays &e predic(ed &ased onconven(ional pa(holo+ic parame(ers andpa(ien( per'ormance s(a(!s. 6o da(e, (hereare no idely accep(ed /idney cancer&iomar/ ers (ha( o!ld s(ra(i'y pa(ien(s in(ohi+h ris/ +ro!ps, al(ho!+h research ison+oin+ and many po(en(ial mar/ ers have&een descri&ed. $> 1ome o' (he more promisin+ mar/ers e%amined in RCC involve (hemolec!lar mechanisms associa(ed i(h (hehypo%ia ind!ci&le pa(h ay, cell!larproli'era(ion, cell cycle re+!la(ion, andcell!lar adhesion 6a&le 35. 6he hypo%iaind!ci&le pa(h ay appears (o play animpor(an( role in an+io +enesis, pH con(rol,cell!lar proli'era(ion, and apop(osis o' common cancers and also may &e impor(an('or (!mor adap(a(ion (o hypo%icenvironmen(s. $?

    Researchers 'rom (he a(ional "ns(i(!(eso' Heal(h charac(eri ed (he loss o' (he shor(arm o' chromosome 3 F3p5 as (he loc!s o' (he von Hippel Linda! VHL5 +ene. $@

    Appro%ima(ely 709 o' pa(ien(s i(h sporadic/idney cancer e%hi&i( VHL +ene dele(ions,and an addi

    Table 2. — Pathologic R isk F actors f or R CC Progression and Survival

    Lower Risk

    TNMpT1a tumors ( ≤ 4 cm , conned to kidney)pT1b tumors ( > 4 cm , but ≤ 7 cm , conned tokidney) pT2 tumors ( > 7 cm, limited to kidney)with low-grad e (I or II) features

    Furhman g rade I and grade II

    HistologyChromophobe renal carcinomas

    Higher Risk

    TNMpT2 tumors ( > 7 cm, limited to kidney) w ith high-grade (III or IV) featurespT3a tumors ( extension through renal capsule i nto p erinephric

    or pe risinuous f at or adrenal, not beyond Gerota’s f ascia)pT3b tumors ( gross ex tension into renal vein or segm ental

    branches, or ext ension into infradiaphragmatic I VC)

    pT3C tumors (ext ension into supradiaphragmaticIVC, or IVC wall invasion)pT4 tumors ( extension beyond G erota’scapsule, adjacent organ involvement)pT any N + tumors

    Furhman grade III and

    grade I V HistologySarcom atoid differentiation

    Collecting duct car cinomas

    Tumor necr osis

  • 8/16/2019 Jurnal Adjuvan Pada Kanker Ginjal Stadium 2b


    Table 3. — Potential Markers f or R CC

    Hypoxia-inducible pathwayHIF-1 α


    Cell-cycleregulation p53PTEN

    Cellular proliferati onKi-67

    Cellular adhesionEpCAM




    Adapted from Lam JS, Leppert JT, Figlin R A, et al. Role o f molecularmarkers i n the diagnosis an d therapy o f renal cell carcinoma. Urology .

    2005;66:1-9. Reprinted with p ermission by Elsevier.

    (ional 279 o' pa(ien(s have VHL +enesilencin+ &y A me(hyla(ion. 20 Go(h even(sinvolvin+ (he VHL +ene appear (o &e morecommon in pa(ien(s i(h LARCC. 2$ A '!nc(ional VHL +ene re+!la(es e%pression o' several pro(eins incl!din+ hypo%ia ind!ci&le'ac(or $ alpha H"# $ α 5 and vasc!larendo(helial +ro (h 'ac(or V)*#5. ndernormo%ic condi(ions, hydro%yla(ed 'orms o' H"# $ α are &o!nd (o (he VHL +ene, hichleads (o rapid de+rada(ion o' (he H"# $ αpro(ein. Eany (!mors incl!d in+ RCC adap(

    (o a hypo%ic environmen(, and !nder s!chcirc!ms(ances, !nhydro%yla(ed 'orms o' H"#$ α do no( &ind (o VHL +enes and (h!s escapede+rada(ion. Hypo%ia as ell as VHLm!(a(ions, VHL dele(ions, and VHL +enesilencin+ &y A me(hyla(ion all have (he

    capa&ili(y o' !pre+!la(in+ H"# $ α in pa(ien(si(h RCC, leadin+ (o in(racell!laracc!m!la(ion o' (his &iomar/er. pre+!la(iono' H"# $ α also leads (o !pre+!la(ion o' V)*#,an impor(an( 'ac(or 'or an+io+enesis. $>

    Car&onic anhydrase "- CA"-5 is ano(herpromis in+ &iomar/er descri&ed 'or RCC.

    VHL +ene m!(a(ions and hypo%ia ind!ce (hee%pression o' CA"-, hich is a cancerassocia(ed (ransmem&rane en yme (ha(ca(aly ses (he in(erconversion &e( eencar&on dio%ide and &icar&ona(e and serves (ore+!la(e in(racell!lar and e%(racell!lar pH

    d!rin+ periods o' hypo%ia in (!mor cells.CA"- is (ho!+h( (o play a role in re+!la(in+cell! lar proli'era(ion and possi&ly cell!laradhesion via (he cadherin and ca(enin'amilies o' adhesion molec!les. 22 CA"- is a(!mor associa(ed an(i+en homolo+o!s (o (he*270 an(i+en 'o!nd on chromosome @p$2F@p$3. *270 monoclonal an(i&odies have &eendeveloped 'or ad8!van( (herapy (rials and 'or(rials in pa(ien(s i(h me(as(a(ic disease. 23

    CA"- is selec(ively e%pressed in +rea(er (han?09 (o @09 o' primary and me(as(a(icRCCs, hereas li((le (o no e%pression isde(ec(ed in nor mal renal (iss!e. 24 2: G!i e(al 27 'o!nd (ha( decreased e%pression o' CA"-res!l(ed in a orse pro+nosis 'or

    July 2 006, Vo l. 13, No. 3 Cancer Control 201

    pa(ien(s i(h me(as(a(ic clear cell RCC. 6hissame +ro!p o' researchers la(er repor(ed(ha( CA"- and Ki :> on m!l(ivaria(e analysis

    ere independen( si+niBcan( predic(ors o' s!rvival. 2> Ki :> is a !&i !i(o!s n!clearan(i+en in all cyclin+ h!man cells and is amar/er 'or cell!lar proli'era(ion. "ncreased

    Ki :> e%pression has &een correla(ed i(hmore a++ressive cancers and has &eendescri&ed as a pro+nos(ic indica(or o' hi+hris/ 'ea(!res in RCC. 2> 3$

    Advances in (iss!e microarray(echnolo+ies have accelera(ed (heiden(iBca(ion o' o(her po(en(ial pro+ nos(ic&iomar/ers incl!din+ +elsolin an ac(in&indin+

    vimen(in an in(ermedia(eBlamen( pro

    (ein5, 32 and p73. 33 (her po(en(ial pro+nos(ic

    mar/ers incl!de cell!lar adhesion molec!les'rom (he cadherin and in(e+rin 'amilies, mos(no(a&ly cadherin :, 34 ) cad herin, 37 cadherin, and vario!s alpha in(e+rins. 3:Ca(enins are cy(oplasmic pro(eins (ha(mod!la(e cad herin '!nc(ion and lin/ cadherins (o (he cell!lar cy(os/ele(on.

    ecreased ca(enin e%pression mi+h( '!r (herdes(a&ili e cell!lar adhesion. 2:

    Com&inin+ molec!lar mar/ers i(hes(a&lished clinical predic(ors o' pro+nosis inpa(ien(s i(h LARCC and me(as(a(ic RCC (opredic( disease speciBc s!rvival has &eenaccomplished in nomo+ram 'orma(. $> 1!chmolec!lar proBlin+ ill 'acili(a(e (he a&ili(y (oacc! ra(ely predic( pa(ien(s des(ined (oe%perience disease rec!rrence and allophysicians (o &e((er (ar+e( pa(ien(s 'orad8!van( (rials.

    pro(ein5, 3$

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    Clinical Series of LARCC

    #ran/ and associa(es $4 repor(ed on $,?0$pa(ien(s i(h !nila(eral clear cell RCC

    (rea(ed i(h radical nephrec (omy 'rom $@>0(o $@@?. 6he mean 'ollo !p in (his pa(ien(series as @.> years. 6he avera+e pa(ien( a+e

    as :2.7 years ran+e 24F?@ years5 and (heavera+e si e o' (he (!mor as >.3 cm ran+e0.?F24 cm5. 1i%(y 'o!r percen( o' pa(ien(s

    ere men, 7?9 had a smo/in+ his (ory, 7.39had recen( onse( o' hyper(ension, and >2.49

    ere symp(oma(ic a( presen(a(ion. 6hees(ima(ed $ , 3 , 7 , > , and $0 year cancerspeciBc s!rvival ra(es 'or all pa(ien(scom&ined ere ?:.:9, >49, :?.>9, :3.?9,and :09, respec(ively. 6he avera+e (ime 'romradical nephrec(omy (o dea(h 'rom clear cellRCC as 3.2 years median $.> years, ran+e0F2: years5. 6he a!(hors concl!ded (ha( (he6 E s(a+e, (!mor si e, +rade, and his(olo+ic(!mor necrosis ere si+niBcan(ly associa(ed

    i(h cancer speciBc s!rvival and desi+ned ascorin+ sys (em 11"* ; s(a+e, si e, +rade,necrosis5 &ased on (hese 'ea(!res (ha( can &e!sed (o predic( o!(come.

    Recen(ly, Kim and collea+!es 3> repor(edon $,$@$ pa(ien(s (rea(ed 'or RCC &e( een

    $@?@ and 200$. A (o(al o' 22: pa(ien(s $@95had clinically locali ed RCC 0 E05 and!nder en( a nephrec(omy and (!mor

    (hrom&ec(omy. ' (he $,$@$ pa(ien(s, $$>$095 had renal vein only involvemen(, $0@@95 had involvemen( o' (he in'erior vena

    cava "VC5, and 20> $>95 had only invasiono' (he perinephric 'a( 63a5 i(ho!( (hrom&!s. 6his cohor( o' 22: pa(ien(s i(h (!mor

    (hrom&!s as compared (o :74 pa(ien(s 0E05 i(ho!( (!mor (hrom&!s ho !nder en(nephrec(omy alone. "n a !nivaria(e analysis,

    veno!s (hrom&!s as a si+niBcan( predic(or'or rec!rrence ha ard ra(io 2.$:, 1 < .00$5.Ho ever, veno!s involvemen( as no( apredic(or 'or rec!rrence in a m!l(ivaria(eanalysis con(rollin+ 'or #!hrman +rade, p6s(a+e, and )as(ern Coopera(ive ncolo+y*ro!p )C *5 per'ormance s(a(!s. A comparison o' (he ris/ o' rec!rrence &ased onlevel o' veno!s involvemen( renal vein(hrom&!s, "VC (hrom &!s &elo (hediaphra+m, "VC (hrom&!s a&ove (hediaphra+m5 did no( reveal a si+niBcan(di erence. "n pa(ien(s i(h locali ed RCC,disease speciBc s!rvival 115 as similar 'orpa(ien(s i(h e%(racaps!lar

    p63a5, renal vein 63&5, and "VC involvemen(&elo (he diaphra+m 63&5 1 = .73:5. 11ra(es 'or 63& and 62 ere si+niBcan(lydi eren( 1 = .0$>5, and 11 ra(es 'or "VC(hrom&!s &elo (he diaphra+m 63&5 and

    veno!s (hrom&!s a&ove (he diaphra+m 63c5

    ere si+ niBcan(ly di eren( 1 = [email protected](ien(s i(h 63c "VC involvemen( had asi+niBcan(ly orse s!rvival ra(e even a'(ercon(rollin+ 'or #!hrman +rade and )C *per'ormance s(a(!s in a m!l(ivaria(e analysis 1 = .0205. #or pa(ien(s i(h me(as(a(ic RCC,(he overall 2 year 11 ra(e as 439. Veno!sinvolvemen(, re+ardless o' (he level o' (he(hrom&!s, did no( si+niBcan(ly a ec( 11 1 = .?345 in pa(ien(s i(h me(as(a(ic disease. A separa(e repor( 'rom (he same ins(i(!(ionrevealed (ha( mos( pa(ien(s i(h (!mor(hrom&!s presen(ed i(h advanced s(a+es o' cancer. 1i%(y (hree percen( o' pa(ien(s i(h

    veno!s involvemen( presen(ed i(hme(as(ases (o re+ional lymph nodes ordis(an( si(es. "n 0 E0 cases i(h "VC (!mor(hrom&!s, caps!lar pene(ra(ion, collec(in+sys(em invasion, and e%(ension in(o (hehepa(ic veins ere more impor(an(pro+nos(ic varia&les (han (he level o' "VC(hrom&!s. 3?

    6he impor(ance o' primary (!morhis(olo+y on (he presence o' renal vein and

  • 8/16/2019 Jurnal Adjuvan Pada Kanker Ginjal Stadium 2b


    "VC (!mor (hrom&!s e%(en sion as repor(ed&y Ra&&ani and collea+!es 3@ in a s(!dy o' $,0?2 pa(ien(s i(h nonme(as(a(ic RCC oroncocy(oma. Renal vein e%(ension aspresen( in :0 pa(ien(s 7.495 and "VCe%(ension as presen( in 3$ 2.?95

    s!&hepa(ic in 27, s!prahepa(ic in 7, andin(ra a(rial in $5. 6he his(olo+ic (ypeassocia(ed i(h an increased ris/ o' renal

    veinI"VC e%(ension as conven (ional clearcell RCC ?0 o' >02 cases, 1 < .000$5, andhis(olo+ic (ypes associa(ed i(h a decreasedris/ ere oncocy(oma 0 o' $$> cases, 1 < .000$5 and papillary his(olo+y 0 o' $4:, 1 < .000$5. Chromopho&e, collec( in+ d!c(,!nclassiBed, and mi%ed his(olo+ies eredemons(ra(ed in $$> pa(ien(s and acco!n(ed'or $$

    202 Cancer Control July 2 006, Vol. 13, No. 3

    Table 4. — Five-Year D isease-Specic S urvival (DSS) for

    Patients With RCC and IVC Tumor Thrombus

    Study Year No. of 5-Year DSS (%)Patients M(–) M(+)

    Skinner et al 46 1989 56 47 0

    Novick e t al47

    * 1990 43 64 11Thrasher and Paulson 48 1993 44 69 0

    Swierzewski et al 49 1994 100 64 20

    Zisman e t al 38 ** 2003 207 72 41

    Parekh et al 50 2005 49 42 20M = metastases* 3-year DDS reported** 5-year DSS for M (–) pa tients, 2-year D SS for M (+) patients

    cases o' renal vein ?5 and "VC 35 (!mor(hrom&!s. 6hey concl!ded (ha( renal vein or"VC e%(ension alone did no( impar( a orsepro+nosis independen( o' (!mor si e, nodals(a(!s, and his(olo+y. 3@

    "n mos( s(!dies, (he presence o' lymphnode or dis (an( me(as(ases re

  • 8/16/2019 Jurnal Adjuvan Pada Kanker Ginjal Stadium 2b


    Surgery and Surgical Adjuncts for LARCC

    Renal Vein and Inferior VenaCava Tumor ThrombusHis(orically, LARCC i(h "VC (!mor (hrom&!s

    as !ni 'ormly le(hal, i(h a 7 year s!rvivalra(e o' only $79 in pa(ien(s ho !nder en(radical nephrec(omy 'or clini cally locali ed(!mors. 4$ 43 Ho ever, improvemen(s inperiopera(ive moni(orin+, in(raopera(ivemana+emen(, and vasc!lar &ypass (echni !eshave allo ed pro+res sively more di ic!l((hrom&!s cases (o &e mana+ed i(h lo ercomplica(ion ra(es. 44,47 #!r(hermore, i( has&een demons(ra(ed (ha( pa(ien(s i(h veno!s(!mor (hrom&!s &!( i(ho!( nodal or dis(an(me(as(ases have +ood oncolo+ic o!(comesand (here'ore meri( a++res sive s!r+ical(rea(men( 6a&le 45. 3?,4: 70 6he 'easi&ili(y o'

    veno!s (!mor (hrom&ec(omy 'or RCC arisin+in a soli (ary /idney has also &eendemons(ra(ed. 7$,72

    6he s!r+ical approach 'or pa(ien(s i(h(!mor (hrom&!s depends on (he level o' (he(hrom&!s 6a&le 75. Pa(ien(s i(h

    s!pradiaphra+ma(ic (!mor (hrom&!s presen(+rea(er (echnical challen+es 'or (he s!r+ical(eam. 6h!s, i( is impera(ive (o de(ermine andclassi'y ho m!ch o' (he "VC is involved &y(hrom&!s. Pri(ch e(( e( al 73 iden(iBed (hree+ro!ps; s!&hepa(ic (hrom&!s, (hrom&!s

    e%(endin+ in(o (he in(rahepa(ic orre(rohepa(ic vena cava &elo (he diaphra+m,and s!pradiaphra+ma(ic (hrom&!s #i+!re5.

    6radi(ionally, a ri+h( (horacoa&dominalincision as (he incision o' choice.6herea'(er, s!r+eons discovered (headvan(a+es o' a chevron incision i(h or

    i(ho!( a midline a&dominal cephalad 6e%(ension and liver mo&i li a(ion via (heLa+en&!ch mane!ver hen (he (hrom&!s isin'radiaphra+ma(ic and hen e%pos!re o' (here(ro hepa(ic vena cava is necessary. 74

    A&dominal incisions and liver mo&ili a(ionallo 'or earlier recovery, ca!se less pain,and elimina(e (he need 'or (horacic drains. "' (he (!mor (hrom&!s e%(ends a&ove (hediaphra+m, a (horacoa&dominal incision or amidline s(erno(omy com&ined i(h ana&dominal incision may &e re !ired.

    Table5. —Levelof IVC


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    Thrombus Level Incision Type Technique CPB or Venovenous Bypass

    Infrahepatic subcostal IVC isolation nomidline thrombectomychevron

    chevron + xiphisternalIntrahepatic chevron IVC isolation usually no

    chevron + xiphisternal control hepatic veinsmidline Pringle maneuver

    thoracoabdominal thrombectomySupradiaphragmatic sternotomy + abdominal IVC isolation usually ye s

    chevron + xiphisternal control hepatic veinsthoracoabdominal Pringle maneuver

    thrombectomymilk/extract t umor from atrium

    CPB = cardiopulmonary bypass

    July 2 006, Vol . 13, No. 3 Cancer Control 203

    a b c

    Level of I VC thrombus (a = infrahepatic, b = intrahepatic orretrohepatic, c = suprahepatic). From Dubernard J-M , Abbou C,eds. Chirurgie Urologique . Paris, France: Masson SA; 2001.Reprinted with permission from Elsevier.

    (her advancemen(s in s!r+ical(echni !es have &een descri&ed 'ormana+in+ "VC (!mor (hrom&!s 'ollo in+repor(s o' improved pa(ien( s!rvival a'(era++ressive s!r+ical resec(ion o' (hese(!mors. 77 Cardio p!lmonary &ypass has &een!(ili ed as an ad8!nc( (o removin+ cavoa(rial(!mor (hrom&!s i(h 7:,7> and i(h o!( 7?,7@

    hypo(hermic circ!la(ory arres(. 6headvan(a+es o' &ypass and circ!la(ory arres(incl!de care'!l, con (rolled dissec(ion inessen(ially &loodless s!r+ical Belds. Ho ever,(here are associa(ed ris/s o' solid or+anischemia, ne!rolo+ic se !elae, andcoa+!lopa(hy i(h (hese (echni !es. #or(!mors i(h minimal (hrom&!s in (hes!pradiaphra+ma(ic loca(ion or 8!s( &elo(he diaphra+m, venoveno!s &ypass via ash!n( crea(ed &e( een (he 'emoral orsapheno!s vein (o (he a%illary vein can &e a

    !se'!l (echni !e (o allo (he s!r+ical (eam (oavoid cardiop!lmonary &ypass. 6his(echni !e can decrease periopera(ivemor&idi(y and,in some ins(ances, ena&lehepa(ic decompression i(h a reversed por(alsh!n(. hen con(rol o' (he vena cava needs(o &e es(a& lished a&ove (he hepa(ic veins,(hePrin+le mane!ver can &e !(ili ed. 6he livercan !s!ally (olera(e 30 (o 47 min !(es o'

    arm ischemia. 6his amo!n( o' (ime sho!ld&e ade !a(e 'or cavo(omy, (!mor (hrom&!se%(rac(ion, and caval repair &elo (he level o' (he hepa(ic veins here vasc!lar con(rol can&e re es(a&lished. (her !se'!l in(raopera(ive(echni !es 'or caval (hrom&!s incl!dehypo(ensive anes(hesia i(h vasodila(ion and

    colloid adminis(ra(ion:0

    and (ransesopha+ealechocardio+raphy, hich provides real (imedia+nos(ic capa&ili(ies (o de(er mine (hepresence o' (hrom&!s and (o moni(or (hee%(en( o' (he (hrom&!s i(hin (he cava or

    i(hin (he a(rial cham&er. :$

    Inferior Vena Cava Invasion#e renal (!mors e%(end in(o (he "VC, and i(is !ncom mon 'or (he (!mor (hrom&!s (o

    invade (he all o' (he

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    "VC. "( is repor(ed (ha( hen (he "VC ischronically o&s(r!c(ed &y a (!mor (hrom&!s,caval resec(ion pro d!ces minimalpos(opera(ive mor&idi(y. :2 "' colla(eralcirc!la(ion is no( presen(, resec(in+ (he "VCcan &e asso cia(ed i(h severe edema o' (he

    lo er e%(remi(ies.:3

    "n (hisse((in+,recons(r!c(in+ (he "VC sho!ld &econsidered and can &e done i(h apoly(e(ra

    nephrec(omy had posi(ive lymph nodes, and ye( s!r vival as e !ivalen( (o (ha( inpa(ien(s i(h renal vein involvemen( only. "na randomi ed,con(rolled (rial con d!c(ed &y(he )!ropean r+ani a(ion 'or Research and6rea(men( o' Cancer *eni(o!rinary 6rac(

    Cancer *ro!p, (he prevalence o' lymph nodesinvolved &y (!mor as lo , re3 s(!died 774 cases o' RCC dia+nosed a( a!(opsy. nly 7 pa(ien(shad lymph

    204 Cancer Control July 2 006, Vol. 13, No. 3

    node me(as(ases conBned (o (here(roperi(one!m. 6heore(ically, less (han $9o' pa(ien(s 7 o' 7745 mi+h( have &een c!red&y nephrec(omy and lymph node dissec(ionalone.

    Einervini e( al >$ eval!a(ed a series o' $:>

    pa(ien(s, incl!din+ $0? ho ere (rea(edi(h nephrec(omy only and 7@ ho!nder en( nephrec(omy i(h re+ional lymphnode dissec(ion limi(ed (o (he an(erior,pos(erior, and la(eral sides o' (he ipsila(eral+rea( vessel 'rom (he level o' (he renal

    vessels do n (o (he in'erior mesen (ericar(ery. 6he 7 year s!rvival ra(e 'or (he $0?pa(ien(s ho !nder en( nephrec(omy alone

    as >@9, hile 'or (hose ho also !nder en(lymph node dissec(ion (he ra(e as >?9,s!++es(in+ no clinical &eneB(. >$

    "n (he only randomi ed phase """ (rial (o

    address (he &eneB(s o' lymph node dissec(iond!rin+ radical nephrec(omy 'or pa(ien(s i(hresec(a&le nonme(as(a( ic RCC,(he incidenceo' !ns!spec(ed lymph nodes a'(er properpreopera(ive s(a+in+ as only 3.39, andcompli ca(ion ra(es ere similar &e( een (he

    ( o +ro!ps.:?

    Pan(!c/ e( al >4 recen(ly repor(edre(rospec(ive da(a re+ardin+ (he o!(come 'orpa(ien(s !nder+oin+ lymph node dissec(ion'or RCC. espi(e (he addi(ion o' nosi+niBcan( mor&idi(y in pa(ien(s !nder+oin+lymphad enec(omy, (hose i(h clinicallyne+a(ive lymph nodes e%perienced nomeas!ra&le overall or rec!rrence 'rees!rvival &eneB(. #!r(hermore, in (his serieso' @00 pa(ien(s, (he incidence o' re+ionalnodal me(as(ases in (he a&sence o' dis(an(disease as less (han 79 43 o' @00 cases5. "(

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    is li/ely (ha( many o' (hese pa(ien(s ereiden(iBed preopera(ively &y comp!(ed(omo+raphy scans or in(raopera(ively &ys!r+ical e%plora(ion. "n (he remainder in

    hom disease is !nreco+ni ed, i( is 8!s( asli/ely (ha( lymph nodes may &e 'o!nd in (he

    perirenal 'a( and s!rro!ndin+ (he pedicle asalon+ (he +rea( ves sels. Less (han ?9 o' node posi(ive cases in (his s(!dy erediscovered inciden(ally in (he sense (ha(nodes ere 'o!nd in (he pa(holo+ic specimen

    i(ho!( a clin ical impression o' nodalinvolvemen(. Clearly, (he ma8ori(y o' nodeposi(ive cases are iden(iBed prior (o lymphnode dissec(ion.

    A more recen( e%perience presen(ed &yinves(i+a (ors a( (he a(ional Cancer"ns(i(!(e descri&ed $74 pa(ien(s i(hme(as(a(ic RCC ho !nder en( cy(ored!c(ive nephrec(omy prior (o sys(emic(herapy. >2 6hey 'o!nd an ?.7 mon(h medians!rvival in pa(ien(s i(h posi(ive nodes,

    hich as in'erior (o (he $7 mon(h medians!rvival in pa(ien(s i(ho!( node posi(ive disease. #!r(hermore, median s!rvival inpa(ien(s i(h a comple(e lymphadenec(omy

    ?.: mon(hs5 as iden(ical (o s!rvival in(hose i(h an incomple(e resec(ion ?.7mon(hs5. 1!rvival as poor 'or pa(ien(sde(ermined (o &e !nresec(a&le a( (he (ime o'

    s!r+ery 3.3 mon(hs5.CanBeld and collea+!es >7 eval!a(ed a

    series o' 74 pa(ien(s i(h clinical D E0disease and concl!ded (ha( (hese pa(ien(ssho!ld &e (ar+e(ed 'or a++ressive

    s!r+ical resec(ion, 'ollo ed &y clinical (rialso' ad8!van( (herapy (o improve o!(come.6hese recommenda(ions ere &ased on ane%(ended median overall s!rvival o' 20.3mon(hs 'or pa(ien(s i(h node posi(ivedisease in (he a&sence o' dis(an( me(as(ases.

    Pa(ien(s i(h only $ posi(ive lymph nodes!rvived si+niBcan(ly lon+er (han pa(ien(si(h +rea(er (han $ posi(ive lymph nodemedi an 37.> vs $4.7 mon(hs5. Rec!rrences

    appeared rapid ly median 4.@ mon(hs5,s!ppor(in+ (he need 'or an e ec(ive ad8!van((herapy. 6his helps (o deBne (he val!e o' alymphadenec(omy as a (herape!(ic proced!re in pa(ien(s i(h clinical node posi(ivedisease, al(ho!+h a (r!e s!rvival &eneB(canno( &e conBrmed in (he a&sence o' aprospec(ive, randomi ed (rial.

    "n pa(ien(s i(h no dis(an( me(as(ases,(heincidence o' re+ional lymph node posi(ivedisease is lo . :?,>3,>4 Availa&le s!rvival da(ado no( s!ppor( per'ormin+ a ro!(inelymphadenec(omy in pa(ien(s i(h no clinicalor radio+raphic evidence o' nodalinvolvemen(. >: "n pa(ien(s i(h clinicallyposi(ive re+ional lymph nodes and noevidence 'or dis(an( me(as(ases, a lymphnode dissec(ion (heore(ically co!ld render apa(ien( i(ho!( evidence 'or resid!al diseaseand sho!ld &e considered in care'!llyselec(ed pa(ien(s. As (he e%perience i(h

    ne er (ar+e(ed (herapies &ecomes morereadily avail a&le, pa(ien(s i(h comple(elyresec(ed node posi(ive disease and noevidence 'or dis(an( me(as(ases co!ld &econsidered 'or ad8!van( (herapy (rials.

    LARCC With Adjacent Organ Involvement#e pa(ien(s presen( i(h ad8acen( or+aninvolvemen( 'rom direc( (!mor e%(ension

    645. 1!ch pa(ien(s pre sen( i(h pain,+enerally 'rom invasion o' (he pos(eriora&dominal all, nerve roo(s, and paraspino!s

    m!scles. Liver e%(ension is !ncommon, andin(rahepa(ic me(as (ases occ!r more o'(en(han local e%(ension. 6he cap s!les o' lar+e(!mors may inden( and compress ad8a cen(or+an parenchyma &!( seldom ac(!ally +ro&y direc( e%(ension in(o (he liver or spleen.

    !odenal and pancrea(ic invasion is!ncommon, &!( hen presen(, i( heralds apoor pro+nosis. 6he propensi(y 'or (!mors (oparasi(i e vessels may acco!n( 'or e%(ensionin(o (he lar+e &o el, mesen(ery, and colon.

    Geca!se s!r+ical (herapy is (he only

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    e ec(ive man a+emen( 'or (his (ype o' (!mor,e%(ended opera(ions are some(imesindica(ed. Comple(e e%cision o' (he (!mor,incl!din+ e%cision o' (he involved &o el,spleen, or a&dominal all m!scles, is (he aimo' (hera py. )n &loc par(ial hepa(ec(omy is

    rarely c!ra(ive &!( occasionally can &eor(h hile. Par(ial e%cision o' (he lar+e

    primary (!mor, or de&!l/in+, is rarelyindica(ed."n one s(!dy, only $29 o' pa(ien(s ho!nder en( incomple(e e%cision o' locallye%(ensive (!mor ere alive a( $ year. >> Eos(repor(s s!++es( (ha( less (han 79 o' pa(ien(s

    i(h e%(ension in(o ad8acen( viscera s!r vive7 years a'(er s!r+ery.July 2 006, Vo l. 13, No. 3 Cancer Control 205

    Early Renal Artery L igation vs E mbolization1i+niBcan( &leedin+ d!rin+ radicalnephrec(omy can occ!r 'or several reasons.6he /idney is e%(remely vas c!lar and hen(!mor is presen(, neovasc!la(!re cana!+men( (he &aseline vasc!lari(y, anden+or+ed veins readily &leed. "n addi(ion,e%pos!re and li+a(ion o' (he renal hil!m andpar(ic!larly (he renal ar(erial &lood s!pplycan &e impeded &y vasc!lar colla(erali a(ion,re(roperi(oneal lymphadenopa(hy, and lar+e/idney (!mors. Al(ho!+h (he po(en(ial 'or&lood loss seems more common in pa(ien(s

    i(h an "VC (hrom&!s, pa(ien(s i(h lar+ehypervasc!lar (!mors i(h no "VC e%(ensionshare similar clinical charac(eris(ics in (ermso' neovasc!lari(y, veno!s en+or+emen(, anddi ic!l( e%pos!re o' (he renal hil!m.

    6ransca(he(er ar(erial em&oli a(ion 6A)5

    o' (he renal &lood s!pply is a me(hod 'orcollapsin+ (he col la(eral circ!la(ion and has&een !(ili ed 'or (herape!(ic and pallia(ivep!rposes in (he mana+emen( o' LARCC. >?

    6A) has &een advoca(ed 'or some pa(ien(si(h LARCC prior (o !nder+oin+ radical

    nephrec(omy. "n 'ac(, Mielins/i andassocia(es >@ repor(ed overall 7 and $0 years!rvival ra(es o' :29 and 4>9, respec(ively,'or $$? pa(ien(s em&oli ed &e'orenephrec(omy compared i(h 379 and 239,respec(ively, 'or (he ma(ched +ro!p o' $$:pa(ien(s (rea(ed i(h s!r+ery alone 1 = .0$5.Reasons 'or (he s!rvival advan(a+e in (he+ro!p o' pa(ien(s mana+ed i(h preopera(iveem&oli a(ion 'rom (his nonrandomi ed s(!dyare no( clearly !nders(ood, and (he res!l(shave no( &een conBrmed in lar+erprospec(ive randomi ed (rials. Re+ardless,(here con (in!es (o &e de&a(e on (headvan(a+es o' preopera(ive em&oli a(ion o' (he renal ar(ery (o 'acili(a(e s!r+ery. 6hera(ionale 'or em&oli a(ion incl!desdecreasin+ (he si e o' (he primary (!mor,decreasin+ (he si e and (he e%(en( o' a (!mor

    (hrom&!s, and decreasin+ (he n!m &er ande%(en( o' veno!s colla(erals. Po(en(ially, 6A)leads (o increased edema i(hin (iss!eplanes, (here&y 'acili(a(in+ s!r+icaldissec(ion, and 6A) allo s 'or ar(er ialcon(rol hen dissec(ion o' (he renal hil!m iscom promised &y (he previo!sly men(ionedclinical charac (eris(ics o' (!mors in somepa(ien(s i(h LARCC.

    Preopera(ive em&oli a(ion is no( i(ho!(ris/s, incl!din+ a sys(emic reac(ion (oem&oli a(ion consis( in+ o' pain, 'ever, andle!/ocy(osis, em&oli a(ion o' or+ans o(her(han (he (ar+e( or+an e+, &o el, spinal cord,or (he con(rala(eral /idney5, and (!morem&oli a (ion 'rom (he devasc!lari ed "VC(hrom&!s. ?0 ?2 6!&! lar necrosis, renala&scess, and al(ered &lood press!re have also&een repor(ed. ?3 "n addi(ion, a si+niBcan(period o' (ime may &e re !ired (o achieveany meas!r a&le re(rac(ion o' (he (!mor(hrom&!s (o a more 'avor a&le loca(ion i(hin(he "VC prior (o s!r+ery. #or (hese reasons,early li+a(ion o' (he renal ar(ery appears (o&e (he pre'erred me(hod 'or mos( s!r+eonscarin+ 'or pa(ien(s i(h LARCC !nder+oin+nephrec(omy. ?4

  • 8/16/2019 Jurnal Adjuvan Pada Kanker Ginjal Stadium 2b


    Adjuvant Therapies for LARCC

    6he pos(opera(ive period 'ollo in+nephrec(omy is (he ideal se((in+ 'or ad8!van((herapy since (he macroscop ic (!mor &!rdenis minimi ed and also (he imm!nodys'!nc(ion a((ri&!(ed (o (he in si(! primary(!mor is allevia(ed. #or an ad8!van( (herapy(o &e idely accep( ed, i( m!s( &e e icacio!sand ell (olera(ed, i(h 'e local or sys(emicside e ec(s. Ad8!van( (herapies have &eenmore idely e%plored in vario!s o(hercancers incl!din+ &reas(, l!n+, and colon.

    Accr!al o' pa(ien(s (o lar+e randomi ed (rialshas &een di ic!l( d!e (o (he rel a(ivein're !ency o' pa(ien(s i(h LARCCcompared i(h o(her mali+nancies. 6o da(e,(he s!ccess o' ad8! van( (herapy 'or RCC in

    (erms o' (rial e%perience as ell as clinicalo!(come has &een disappoin(in+.

    Radiation, Hormonal Agents, Chemo-therapy, and Inhibitors of Angiogenesis

    "ni(ial res!l(s i(h ad8!van( radia(ion seemed'avora&le in (erms o' decreasin+ localrec!rrence ra(es. ?7 Ho ever, lon+er 'ollo!p as ell as o(her randomi ed, prospec(ives(!dies o' ad8!van( radia(ion compared (o

    o&serva(ion 'ollo in+ nephrec(omy 'orLARCC revealed no di erences in s!rvivaland possi&ly si+niB can( added mor&idi(y (oa&dominal or+ans. ?:,?> Li/e ise, arandomi ed, prospec(ive (rial o' ad8!van(

    medro%ypro+es(erone ace(a(e compared (oo&serva (ion 'or pa(ien(s 'ollo in+nephrec(omy revealed simi lar relapse ra(eso' 339 and 349, respec(ively, a'(er a median'ollo !p o' 7 years. ?? 6he c!m!la(ive o&8ec(ive response ra(e 'or cy(o(o%ic chemo(herapy

    in (he me(as(a(ic se((in+ as :9, andindivid!al (rial response ra(es rarelye%ceeded $09. ?@,@0 6he poor response ra(e'or mos( chemo(herapy re+imens has &eena((ri&!(ed (o P +lycopro(ein, hich is aprod!c( o' (he m!l(idr!+ resis(ance +ene

    E R$5 !ni'ormly e%pressed in RCCs andhich '!nc(ions as an ener+y dependen( dr!+

    eN!% p!mp. @$ Chemo(herapy rela(ed (o%ici(yand, more impor(an(ly, limi(ed e icacy o' chemo(herapies 'or RCC dampens (heen(h!siasm 'or (hese dr!+s as op(ions 'orad8!van( (rea(men(.

    6heore(ically, an+io+enesis inhi&i(orssho!ld have meas!ra&le e ec(s in pa(ien(s

    i(h /idney cancer &eca!se mos( pa(ien(si(h clear cell RCC have a m!(a (ion in (he

    VHL +ene (ha( s(a&ili es V)*#. @2 A conse!ence o' (he loss o' (he VHL +ene is

    !pre+!la(ion o' V)*# via a pa(h ay involvin+acc!m!la(ion o' hypo%ia ind!ci&le 'ac(or.

    V)*# is a po(en( an+io+enic 'ac(or and issecre(ed &y many h!man cancers, &!( clearcell RCC as a +ro!p prod!ces par(ic!larly

    hi+h levels. 1everal an(ian +io+enics have&een s(!died in (he me(as(a(ic se((in+ i(hlimi(ed (o modes( response. @3 @7 Presen(ly,an+io+enesis inhi&i(ors have an !ndeBnedrole in (he ad8!van( se((in+.

    206 Cancer Control July 2 006, Vol. 13, No. 3

    ImmunotherapyPa(ien(s i(h RCC may &eimm!nocompromised a( (he (ime o' dia+nosis. )vidence 'rom animal s(!diess!++es(s (ha( (he primary (!mor ac(s as animm!nolo+ic sin/ (ha( res!l(s in (he

    s!ppression o' cell media(ed imm!ni(y.@:,@>

    6cells appear (o &e more sensi(ive (o (!morind!ced apop(osis,and (hey have impairedin(erle!/in 2 "L 25 pro d!c(ion and "L 2recep(or si+nalin+. @? #!r(hermore,de'ec (ive(!mor an(i+en presen(a(ion and reco+ni(ionmi+h( con(ri&!(e (o (!mor pro+ression andcompromised s!r vival. ephrec(omy canreverse some o' (he imm!ne s!p pression asevidenced &y rare cases o' spon(aneo!sme(as(a(ic (!mor re+ression 'ollo in+primary s!r+ery. )%o+eno!sly adminis(eredcy(o/ines mi+h( a!+men( (!mor speciBc

    imm!ne responses and have &een (he &asis'or (he (rea(men( o' pa(ien(s i(h me(as(a(icRCC.

    6 o cy(o/ines (ha( have &een e%(ensivelys(!died and hich are c!rren(ly availa&le 'orpa(ien(s i(h RCC incl!de "L 2 and in(er'eron

    "# 5. Response ra(es (o"L 2 and "# 'or pa(ien(s i(h me(as(a(icRCC ran+e 'rom $79 (o 209. @0,@@,$00 #o!rrecen(ly cond!c(ed ran domi ed, prospec(ive(rials o' pa(ien(s a( hi+h ris/ 'or cancerrec!rrence addressed (he role o' ad8!van(imm!no(herapy compared (o o&serva(ion'ollo in+ nephrec(omy. $0$ $04 6 o o' (he (rialsemployed di eren( re+imens o' ad8!van( "#α , and ano(her smaller (rial assessed hi+hdose &ol!s "L 2. 6he 'o!r(h (rial incorpo ra(eda com&ina(ion o' o!(pa(ien( "L 2, o!(pa(ien("# α 2a, and in(raveno!s 7

  • 8/16/2019 Jurnal Adjuvan Pada Kanker Ginjal Stadium 2b


    (he (rea( men( arm compared (o o&serva(ion.one o' (he 'o!r prospec(ive s(!dies

    demons(ra(ed improved disease 'ree s!rvivalor improved overall s!rvival i(h ad8!van(cy(o/ine (herapy compared (o o&serva(ion'ollo in+ nephrec(omy. 6o%ici(y i(h ad8!van(

    imm!no(herapy as s!&s(an(ial. "n ( o o' (he(rials, (here as a (rend (o ards improveds!rvival in (he o&serva(ion arms o' (hes(!dies. $0$,$04

    Cell-Based Therapies andVaccine Therapies

    Eany cell &ased adop(ive imm!no(herapyre+imens have &een eval!a(ed in pa(ien(s

    i(h me(as(a(ic RCC incl!din+ lympho/ineac(iva(ed /iller LAK5 cells, (!mor inBl(ra(in+lymphocy(es 6"Ls5, and a!(olympho cy(e(herapies. 6hese (herapies are !s!allyadminis (ered (o+e(her i(h "L 2, &!( (heres!l(s have &een no more 'avora&lecompared (o "L 2 (herapy alone. @? nly onesmall s(!dy revealed a si+niBcan( di erencein pro +ression 'ree s!rvival 'or pa(ien(s horeceived ad8! van( adop(ive imm!no(herapy'ollo in+ nephrec(omy. 6hese pa(ien(s ere(rea(ed i(h a!(olo+o!s lympho cy(esac(iva(ed e% vivo &y an(i C 3 monoclonal

    an(i &ody and a!(olo+o!s cy(o/ines.$07

    Prospec(ive, ran domi ed s(!dies ill &ere !ired (o de(ermine he(her

    cell &ased (herapies have a deBni(ive role asan ad8!nc( (o nephrec(omy in (he locallyadvanced se((in+.

    A poor response (o imm!no(herapy co!ld&e asso cia(ed i(h 'a!l(y presen(a(ion orreco+ni(ion o' (!mor an(i+ens. Cancer cells

    have !ni !e (!mor speciBc an(i +ens, s!ch as(he *270 an(i+en, (ha( are no( (ypicallye%pressed on (he cell s!r'ace o' normal renal(iss!e. 6 lymphocy(es are (he e ec(or cells o' (he imm!ne sys (em and reco+ni e an(i+en(hro!+h (he 6 cell recep(or 6CR5 C 3comple%. 6he &indin+ o' (he 6CR C 3 comple% (o (he (!mor an(i+enIma8orhis(ocompa(i&ili(y comple% EHC5 e%pressedon (he cell s!r'ace o' an(i+en presen(in+ cellss!ch as macropha+es and dendri(ic cells isnecessary 'or 6 cell '!nc(ion. Appropria(e 6cell '!nc (ion res!l(s in (!mor cell lysis, 6 cellproli'era(ion, and cy(o/ine secre(ion."mpaired 6 cell '!nc(ion may impar( a hi+herris/ o' cancer pro+ression.

    Vaccine &ased s(ra(e+ies are on (he'ore'ron( o' (herapies 'or locally advanced/idney cancers. 6he &io lo+ical +oal o'

    vaccine (herapy is (o &ypass (he indirec(s(im!la(ion o' (he imm!ne sys(em andins(ead +enera(e (!mor speciBc G cells andna(!ral /iller cells, as ell as cy(o(o%ic 6lymphocy(es and 6 helper cells (ha( reco+ni e speciBc imm!noreac(ive (!mor an(i+en

    (ar+e(s in con(e%( i(h (he EHC comple% o' an(i+en presen(in+ cells. Eany approacheshave &een !sed (o +enera(e (!mor speciBc

    vaccines. @? Eos( o' (hese s(ra(e+ies have&een eval!a(ed in pa(ien(s i(h me(as(a(icdisease. Ho ever, several vaccine cons(r!c(sare &ein+ eval!a( ed as ad8!van( (herapies.

    ne prospec(ive, randomi ed s(!dyeval!a(ed $20 pa(ien(s ho received ei(hera!(olo+o!s irradia(ed (!mor cells admi%ed

    i(h &acill!s Calme((e *!Orin or ho ereo&served a'(er nephrec(omy 'or RCC p6$F3&, 0 or D5. 6he median 'ollo !p as :$mon(hs, and (here as no si+niBcan(di erence in 7 year disease 'ree s!rvivalra(es :39 'or (he vaccine +ro!p vs >29 'oro&served pa(ien(s5 or 7 year overall s!rvivalra(es :@9 vs >?9, respec(ively5. $0: 1ch a&and associa(es $0> repor(ed (he e ec(s o' anad8!van( vaccine consis(in+ o' irradia(eda!(olo+o!s (!mor cells admi%ed i(h h!manrecom&inan( +ran!locy(e macro pha+e colonys(im!la(in+ 'ac(or *E C1#5 adminis(ered (oa small n!m&er o' pa(ien(s i(h

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    nonme(as(a(ic RCC. Pa(ien( n!m&ers ere(oo small (o dra concl!sions re+ardin+cancer pro+ression or s!rvival. Ho ever,(here as a si+niBcan( increase in peripheral&lood C 4 and C ? 6 cell prec!rsorsmeas!red on (he con cl!sion o' (herapy

    compared (o levels de(ec(ed 2 ee/s prior (o(he s(ar( o' vaccine (herapy.

    6!mor lysa(e has &een !sed as anad8!van( vaccine in a randomi ed,prospec(ive phase """ (rial 'or pa(ien(s i(hp62F3& p 0F3 E0 RCC accordin+ (o (he $@@3

    "CC classiBca(ion sys(em. $0? "n (his s(!dy,

    RCC cells ere harves(ed 'ollo in+nephrec(omy and ere inc! &a(ed i(h "#prior (o cell devi(ali a(ion (o improve

    July 2 006, Vo l. 13, No. 3 Cancer Control 207

    (he an(i+enici(y o' (he cells. nly 49 o' (hepa(ien(s had re+ional node posi(ive disease,and only $9 o' (he pa(ien(s e%perienced

    vaccine rela(ed (o%ici(y. #ollo in+nephrec(omy, many pa(ien(s ere los( a'(erran domi a(ion $>4 o' 773 pa(ien(s, 3295,incl!din+ @@ pa(ien(s ho ere randomi ed(o (he vaccine arm o' (he s(!dy. Al(ho!+h (he

    im&alance o' (he loss crea(espos(randomi a(ion &ias, (he res!l(s o' (he(rial ere never(heless impressive. A( >0mon(hs o' 'ollo !p, (he ha ard ra(io 'or(!mor pro+ression as $.7@ $.0>F2.3:5 in'avor o' (he vaccine +ro!p 1 = .0204, lo+ran/ (es(5, and (he >0 mon(h pro+ression 'rees!r vival ra(e as >29 in (he vaccine +ro!pand [email protected] in (he con(rol +ro!p. A s!&se(analysis 'o!nd no si+niB can( di erence in(he 7 year pro+ression 'ree s!rvival 'orpa(ien(s i(h p62 (!mors. Ho ever, pa(ien(sin (he vaccine +ro!p i(h p63 diseasee%perienced nearly an $?9 improvemen( in7 year pro+ression 'ree s!rvival. Al(ho!+hoverall s!rvival as no( an endpoin( 'or (he(rial,(he res!l(s are enco!ra+in+ and providea concre(e s(ep (o ards implemen(in+ ane ec(ive ad8!van( (hera py 'or pa(ien(s i(hRCC. $0?

    An on+oin+ m!l(icen(er randomi edphase """ (rial 'or pa(ien(s i(h a hi+h ris/ o' rec!rrence 'ollo in+ nephrec(omy 'or RCC $0@

    is inves(i+a(in+ (he !se o' hea( shoc/ pro(ein

    pep(ide comple% @: H1PPC @: An(i +enics"nc, e Qor/, Q5 as an a!(olo+o!s vaccinecompared (o o&serva(ion. H1PPC @: hassho n some e icacy in pa(ien(s i(hme(as(a(ic RCC. $$0 Animal s(!dies s!++es((ha( H1Ps may have a +rea(er &eneB( in anad8!van( se((in+. $$$ H1Ps are hi+hlyconserved pro (eins (ha( chaperone vi(alpep(ides (hro!+h vario!s in(racell!larcompar(men(s i(ho!( &ein+ de+raded. 6hecom&ina(ion o' H1Ps and (heir Jpro(ec(edpep (ides are hi+hly imm!no+enic and have&een no(ed (o ac(iva(e C ? and C 4

    lymphocy(es, ac(iva(e na(!ral /iller cells,ind!ce cy(o/ine secre(ion, and s(im!la(edendri(ic cell ma(!ra(ion. $$$

    Targeted Therapies*270 is a (!mor associa(ed an(i+enhomolo+o!s (o CA"- (ha( is 'o!nd in +rea(er

    (han @09 o' clear cell RCCs &!( is a&sen( onnormal renal (iss!e. - *270 c*270,Rencare%5 is a chimeric "+*$ an(i&ody (ha(&inds (o CA"-. - *270 has demons(ra(edac(ivi(y in me(as(a(ic RCC as a sin+le a+en((herapy and hen com&ined i(h o(her&iolo+ical response modiBers s!ch as "L 2."n(eres( in c*270 as an ad8!van( (herapy 'orLARCC is &ased no( only on (he responsera(es in pa(ien(s i(h me(as(a(ic RCC ran+in+'rom 279 (o 429, &!( also on i(s 'avora&le(o%ici(y proBle. $$2 6he AR"1)R (rial Ad8!van(Rencare% "mm!no(herapy Phase """ 6rial (o1(!dy ) icacy in onme(as(a(ic Renal CellCarcino ma5 is an on+oin+ phase """randomi ed, do!&le &lind, place&o con(rolled(rial 'or pa(ien(s i(h )C * per'or mances(a(!s o' 0 i(h comple(ely resec(ed primary

  • 8/16/2019 Jurnal Adjuvan Pada Kanker Ginjal Stadium 2b


    clear cell RCC and no evidence o' remainin+local or dis(an( disease.

    6he 1 #ood and r!+ Adminis(ra(ionrecen(ly approved ( o oral m!l(i /inaseinhi&i(ors (ha( (ar+e( several recep(or(yrosine /inases incl!din+ V)*# recep (or

    and pla(ele( derived +ro (h 'ac(or recep(or.Go(h s!ni(ini& 1!(en(5 and sora'eni&e%avar5 have demon s(ra(ed si+niBcan(

    ac(ivi(y in pre(rea(ed me(as(a(ic RCCpa(ien(s. $$3,$$4 6o%ici(y o' &o(h a+en(sappears accep( a&le in (he me(as(a(ic se((in+.

    As clinical e%perience evolves i(h (hese(ar+e(ed (herapies, ad8!van( (herapy (rials

    ill mos( cer(ainly &e accomplished and (h!smay e%(end pro+ression 'ree s!rvival andoverall s!rvival 'or pa(ien(s i(h locallyadvanced nonme(as(a(ic disease.


    6here have &een si+niBcan( advances in (heperiopera (ive and in(raopera(ivemana+emen( o' pa(ien(s i(h LARCC,par(ic!larly in (he eval!a(ion and (rea(men(o' pa(ien(s i(h "VC (!mor (hrom&!s.Pa(ien(s i(h LARCC have an eleva(ed ris/ 'or disease rec!rrence, and com ple(eresec(ion o' (he primary (!mor is cri(ical 'orlon+ (erm s!rvival. ever(heless, (radi(ionalclinical and pa(holo+ic charac(eris(ics o' pa(ien(s primary (!mors do no( al ayspredic( (he &iolo+ical &ehavior o' (heirmali+nancies or (heir e%pec(ed diseasespeciBc s!rvival. 6he las( 'e years have

    i(nessed a (remendo!s s!r+e in (he

    iden(iBca(ion o' molec!lar mar/ers e+, CA"-, vimen(in, p73, +elsolin, Ki :>, H"# $ α ,V)*#5(ha( can &e incorpora(ed in(o modelsalon+side p6 E s(a+e, )C * s(a(!s,#!hrman +rade, and (!mor necrosis, (oenhance o!r a&ili(y (o (ar+e( pa(ien(s a( ris/

    'or disease rec!r rence. Randomi ed (rials o' ad8!van( radia(ion, hormon al (herapy and,more recen(ly, imm!no(herapy have sho nno clinical &eneB(. A!(olo+o!s (!mor

    vaccines may decrease rec!rrence ra(es 'orpa(ien(s i(h LARCC, &!( addi(ionalprospec(ive, randomi ed s(!dies need (o &e!nder(a/en. 6he res!l(s o' ( o on+oin+ad8!van( (her apy (rials H1PPC @: and -*2705 are ea+erly a ai(ed. #!(!re (rea(men(s(ra(e+ies 'or pa(ien(s i(h LARCC ill li/elyincorpora(e a++ressive s!r+ical resec(ion'ollo ed &y com&ina(ions o' (herapies (o

    incl!de cy(o/ines, vac cines, inhi&i(ors o' an+io+enesis, and possi&ly some o' (he ne ersmall molec!le (ar+e(ed (herapies c!rren(ly&ein+ eval!a(ed in pa(ien(s i(h me(as(a(icRCC.


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