Jurnal Adjuvan Pada Kanker Ginjal Stadium 2b

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

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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.


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/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.

Introduction

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'


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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+


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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


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Table 3. — Potential Markers f or R CC

Hypoxia-inducible pathwayHIF-1 α

VEGFCAIX

Cell-cycleregulation p53PTEN

Cellular proliferati onKi-67

Cellular adhesionEpCAM

Cadherins

Catenins

MiscellaneousVimentinGelsolin

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


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"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 $$


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


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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

TumorThrombusandSurgicalApproach


9/19

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


10/19

"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


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. "(


11/19

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


12/19

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


13/19

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+.


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


14/19

(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


16/19

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.

Conclusions

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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