livraghi 2011 treatment opt hcc

7/29/2019 Livraghi 2011 Treatment Opt HCC

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Scandinavian Journal o Surer 100: 2229, 2011

TreaTmenT opTions in hepaTocellular carcinoma Today

T. lvg1, h. mk2, p.-d. l3

1 Interventional Radiolo Deartment, Istituto Clinico Humanitas, Rozzano, Milano, Ital2 Deartment o Surer, Helsinki Universit Hosital, Helsinki, Finland3 Deartment o Oran Translantation, astroenterolo and nehrolo, Oslo Universit Hosital,

Oslo, Norwa

absTracT

ht (hcc) t t t t t

ww. a v 90% hcc t v vtv t -v v t t t wt g v ttb c t . p g hcc w vt gt t . Tgt t wt q t (rFa), t t(hr), v ttt (lT), ttt t t (Tace) t v t vt. T tgt t ttwt hcc t g g. a tt wt t t v v w g t tt wt g t tv v vt tv hr. T t ttt t t z t t, t tg t f t vt v t t.

Ke words: HCC; heatocellular carcinoma; radiorequenc ablation; ercutaneous ablation rocedures;ercutaneous ethanol injection; intra-arterial thera; transcatheter chemoembolization; liver resection;liver translantation

Corresondence:Heikki Mkisalo, M.D.Deartment o SurerHelsinki Universit HositalFI - 00029, Helsinki, FinlandEmail: heikki.makisalo@hus.

infuence o HCV inections transmitted beore 1990the incidence o HCC could be exected to declineater 510 ears in the Western Euroe. Thus, themetabolic sndrome, diabetes, non-alcoholic steato-heatitis, and excessive alcohol consumtion ma bethe main risk actors o HCC in the uture.

Due to HCCs rim ronosis, there has been a

reat research eort made in order to come u withecient theraeutic strateies to cure this disease.Like most other solid tumours, surer las a un-damental role in its treatment. Surical resection(HR), local ablation theraies, and liver translanta-tion (LT) are rearded as otentiall curative treat-ment modalities deendin on the size and numbero tumors. It is estimated that curative treatment witheither HR or radiorequenc ablation (RFA) can beoered onl to 10% o all HCC atients havin 3 orewer 3 cm or smaller HCCs (3). However, with rou-tine screenin o hih-risk atients more earl HCCcases are oin to be dianosed allowin radicaltreatment.

INTRODUCTION

Heatocellular carcinoma (HCC) ranks th amonthe most revalent cancers in the world and is thethird most common cause o cancer related mortalit(1). There is a marked variation in occurrence o HCCamon eorahic reions and between men and

women. The latest ae-adjusted annual incidencerates er 100.000 in men are 13 in Ital and 2 to 4 inthe Nordic countries (2). The resective ures inemales were 3 in Ital and 1 to 2 in the Nordic coun-tries. Alon with HBV vaccination and with declinin


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23Treatment options in hepatocellular carcinoma today

LT has been oered to selected atients with HCC.However, u until the mid nineties, the results weredisaointin with reorted overall ve-ear sur-vival rates ranin rom 30 to 40%. In 1996, Mazza-erro and co-workers ublished a ivotal aer, dem-onstratin excellent 4-ear survival data and low re-currence rates in atients with earl stae, unresect-able HCC (4). This led to the ormation o the loballutilised Milan criteria (solitar tumour less than 5 cmor u to three nodules each less than 3 cm) or select-in HCC atients to LT.

STAgINg SySTEMS

The urose o stain HCC tumours is to classieach case accordin to a certain redictable ronosiswith otimal treatment. Stain is usuall based ondianostic radioloical morholo. Classicall, theTNM sstem has been utilised or classication osolid tumours and is as ollows in HCC; T1: 1 nodule

< 2 cm, T2: 1 nodule u to 5 cm or 3 nodules u to 3cm, T3: one or more tumours > 5 cm, and T4: tumourextendin into neihbourin orans.

The sinicance o the liver unction requires amore comlex clinical classication sstem as a basisor theraeutic allocation. The Barcelona Clinic LiverCancer (BCLC) stain sstem (Fi. 1) (5) is the onlvalidated sstem which includes in addition to tumorburden atients erormance status and liver unc-tion when determinin the ronosis ater the treat-ment (6).

BCLC THERApEUTIC FLOW-CHART

BCLC theraeutic fow-chart or HCC atients (Fi.1) and its recommendations, because endorsed bEASL (the Euroean Association or the Stud o theLiver) and AASLD (American Association or theStud o Liver Disease), are the most alied world-wide (7). The main recommendations adoted bEASL and AASLD are:

a) patients who have a sinle lesion can be oeredsurical resection in the resence o cirrhosis withreserved liver unction, normal bilirubin and he-atic vein ressure radient < 10 mm H.

b) LT is an eective otion or atients with HCCcorresondin to the Milan criteria.

c) Local ablation is a sae and eective thera oratients who cannot undero resection, or as abride to translantation. Alcohol injection andradiorequenc are equall eective or tumours< 2 cm. However, the necrotic eect o radiore-quenc is more redictable in all tumour sizes.

d) No recommendations can be made reardin ex-andin the listin criteria beond the standardMilan criteria.

e) TACE (transcatheter arterial chemoembolisation)is recommended as rst line non-curative theraor non surical atients with lare-multiocalHCC who do not have vascular invasion or extra-heatic sread.

) Sstemic or selective intra-arterial chemotherais not recommended and should not be used asstandard cure.

Fi. 1. The Barcelona Clinic Liver Cancer (BCLC) stain sstem. Modied rom Llovet et al (5).

HCC

Stage DOkuda 3, Child C, PST >2

Stage A-COkuda 1-2, Child A-B, PST 0-2

Stage 0Okuda 1, Child A, PST 0

Very early stage (0)Single < 2 cm

Carcinoma in situ

Early stage (A)Single or 3 nodules

< 3 cm, PST 0

Intermediate stage (B)Multinodular, PST 0

Advanced stage (C)Portal invasionN1, M1, PST 1-2

Stage DTerminal

Single 3 nodules, d 3 cm

Portal pressure/

bilirubin increased

Yes Associated diseases

No

Portal invasion, N1, M1

No Yes No Yes

Resection Liver transplantation PEI/RFA TACE New agentsSymptomatic

treatment


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24 T. Livraghi, H. Mkisalo, P.-D. Line

IS THE BCLC FLOW-CHART STILL VALID?

The strictness o rotocols or cancer treatment is uni-versal and the BCLC theraeutic fow-chart is not anexcetion. However, heteroeneit o HCC resenta-tions toether with the variable stae o cirrhosismiht require a less dened strate. Furthermore,based on articular theraeutic exerience and tech-nical imrovements and renements, some leadincentres in recent ears have queried certain BCLC/AASLD treatment allocations and roosed dierentstrateies.

In our oinion, with reard to ercutaneous abla-tion theraies (pATs) such as ercutaneous RFA orethanol injection (pEI), and to intra-arterial theraies(IATs) such as TACE, BCLC/AASLD uidelines couldcurrentl be modied as ollows.

STAgE 0 tumours include carcinoma in situ or verearl sinle tumours smaller than 2 cm in diameter.The liver disease is not worse than Child-puh classA cirrhosis and the atient should be ull active(erormance status, pST 0). This stae is distin-

uished rom the stae A o the lack or rarit oerinodular neolastic invasion. patholoical seci-mens describe a well-dierentiated nodule with in-distinct marins (the so-called indistinct te) thatcontains bile ducts and ortal veins, to which theradioloical attern well correlates showin ortalblood sul without tumour stainin. To be exact,in relation to the local invasiveness, the correct cut-oo ver earl stae should have been xed at 1.5 cmin size. In act atholoists, between 1.52.0 cm, de-scribe nodules (the so-called distinct te or smalladvanced te) containin zones o less dierenti-ated tissue with more intense rolierative activitthat ive rise to ortal microinvasion or microsatel-

lites in 1020% o the cases (usuall within 10 mm othe nodule). Increasin the diameter, the rate o mi-croinvasion increases roortionall, i.e. 3060% innodules 25 cm and u to 6080% above 5 cm o size(8, 9).

When easible, HR is considered the treatment ochoice in atients who are not candidates or LT. Thisstatement was not based on randomized controlledtrials (RCTs) vs other otions, but on the oncoloicalassumtion that HR is the more suitable otion orobtainin comlete tumour ablation with saetmarins around it. This statement was establishedin site o several cohort studies comarin HR andpATs that ailed to demonstrate better results in a-

vour o HR (1013). Now some RCTs are available, allrevealin that OS rates in atients with earl HCC aresimilar ater pAT (rinciall RFA) and HR (1416).In ver earl HCC, due to the smaller tumour size,RFA should robabl oer even better overall sur-vival (OS) because o its hiher local ecac than inearl HCC.

Are the saet marins around the tumour moresae with HR than RFA when treatin ver earltumours? Aimin to a saet marin RFA obtained asustained comlete resonse in 97.2% o 218 cases(17). Accordin to the histoatholoical stud o Sa-saki onl one case o ver earl HCC out o 100cases resented a microsatellite more than 10 mm

distant (18). O course, the best wa to determinewhether RFA is more eective than HR or verearl stae would obviousl be b direct comari-son in a RCT. However, the results in the studies re-viewed above indicate that the dierence between thetwo aroaches is airl small, and the samle sizerequired to ensure meaninul results is quite lare.For this reason a trial o this sort is robabl not ea-sible. To ive shae to such a trial a recent Markovmodel analsis was alied (19). Its conclusion wasthat RFA ollowed b HR or the ew cases o initiallocal treatment ailure was nearl identical to HR re-ardin OS, even with the best scenario or HR andthe worst scenario or RFA. Albeit under an equiva-lent OS, RFA oers lower comlication rate, nelii-ble erioerative mortalit, lower ablation o non-neolastic tissue, and lower costs b reducin treat-ment times, hosital sta, material used, and need orblood transusions.

All the studies comarin RFA to pEI were in a-vour o RFA, in terms o shortness o treatment, localecac, OS and disease ree survival, while the onl

initial advantae o pEI was the relativel lower com-lications rate (2021). When the learnin curve wasover and the risk conditions were known, the com-lications and mortalit rates comared with thoseo pEI. However, pEI remains recommended in casescontraindicated or RFA and, o course, where RFA isnot available.

In summar, reerrin to oints a and c oAASLD recommendations, there are ood reasons tosuest that RFA should relace HR as theraeuticold standard or atients with ver earl HCC.Furthermore, RFA is reerable to pEI also in HCC < 2cm in that it can obtain hiher local ecac in casesresentin erinodular invasiveness. However, RFA

is comarable to HR onl in centres with a hih ex-erience o the rocedure. The lon learnin-curve oRFA is much more dicult to achieve in countrieswith low revalence o HCC.

Stage A tumours are earl sinle tumours or 3 nod-ules smaller than 3 cm in diameter, Child-puh classis A or B, and pST 0. Althouh demonstratin com-arable OS when comarin HR to pAT (1013), thesecohort studies were fawed b critical drawbacks inbaseline characteristics between the rous, articu-larl reardin the better liver unction or HR a-tients. Severe brosis is not onl associated with ear-lier liver ailure but also with a hiher risk o multi-centric carcinoenesis stronl infuencin the nal

outcomes. Some o these studies comared OS ac-cordin to the number and to the diameter o thenodules as well. Multilicit resulted a avourableactor or atients treated with RFA, robabl be-cause o the hiher loss o nonneolastic tissue aterHR that could anticiate the liver decomensation.

The ecac o RFA is known to be size deendent.Ater pATs, OS o atients with nodules < 3 cm indiameter was hiher than that o carriers o noduleswith a diameter 35 cm. Wh did the RCTs demon-strate that OS rates in atients with earl HCC aresimilar ater pAT (rinciall RFA) and HR, evenwith nodules > 3 cm (1416)? In act, it would be rea-sonable to exect better OS rates amon atients sub-


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mitted to HR, which is seeminl the onl methodcaable o ensurin comlete ablation o nodules ac-comanied b eritumoral microinvasion. The equi-valent outcome robabl refects the comensatoreects o certain advantaes o RFA, i.e. less destruc-tion o normal tissue and lower morbidit rate, withresect to the hiher local ecac o HR.

In summar, there are ood reasons suestinthat RFA should be couled with HR as theraeuticold standard or selected atients with earl HCC,i.e. with Child-puh class B, or with multile tu-mours. With reards to the size, in sinle nodules > 3cm HR remains the rst otion, while in nodules 23cm a eer discussion is advisable, accordin to indi-vidual clinical arameters (ae, site, associated dis-eases, risk conditions) and to the oerators exertise.O course, when the atient is considered inoerable,RFA can be indicated also in hue tumours, even incombination with other rocedures (13,22).

Stage B tumours are intermediate, multinodular tu-mours, and the atients have either Child A or B cir-rhosis and are o pST 0. It is worth emhasizin that

the intermediate stae includes a ver wide raneo tumoural resentations, i.e. rom our small to doz-ens (or uncountable) tumours o various sizes occu-in a lare art o the liver. Such a variet o os-sibilities makes it dicult to comare the trials con-cernin the IAT results. O note, the survival im-rovement ater conventional TACE (cTACE) seemsto be marinal, as one meta-analsis did not nd asinicant OS dierence between treatment versussuortive care alone (23). Unlike some earlier RCTswere in avour o cTACE a more recent RCT was notable to demonstrate an imrovement in OS atercTACE versus inactive treatments (24). The ke clini-cal roblem is whether all atients with intermedi-

ate stae should receive cTACE or onl a subrouo them. To date, cTACE has been considered thestandard otion or atients with intermediatestae, even thouh several imortant issues remainto be claried, includin what is the best chemother-aeutic dru (doxorubicin, cislatin, mitomcin, etc),what is its best dosae, what is the best embolisationaent (elatin sone, autoloous blood clots, ol-vinl alcohol articles, etc), what is the ecac oLiiodol, and what is the otimum time interval orre-treatment (scheduled or on demand). However,the evidence o an additive antitumoural eect withconsequent hiher ecac and better OS o cTACEversus cTAE is unavailable, suestin that ischemia

miht be the more imortant actor inducin tumourresonse ater cTACE. For this reason IAT is a con-tinuous work in roress eld. To imrove themodest, i an, theraeutic ecac o cTACE and toreduce its induced ischemic damae to the non-neo-lastic tissue and its sstemic toxicit, some newtechniques were recentl roosed. TAE with smallsherical embolic articles (25) and TACE with non-resorbable hdroel dru-elutin beads (DEB) caa-ble o bein loaded with anthracclin derivates suchas doxorubicin, seem to oer such advantaes. An-other ossibilit is oered b advancements in mi-crocatheter technolo, which acilitates ultraselec-tive catheterization o nodule eeders and the over-

fow o Liiodol into the ortal vein, a actor associ-ated with lower local recurrence (26).

The multikinase inhibitor soraenib has antianio-enic and antirolierative roerties and is the rstaent to demonstrate a statisticall sinicant im-rovement in OS (27). Soraenib is now considered asstandard care o atients with advanced HCC inman centres to atients havin Child A cirrhosis andood erormance status. Soraenib is also used in anadjuvant settin ater surer or RFA (STORM trial)and combined with TACE (SpACE trial, hase II,www.clinical trials.ov).

Reerrin to oint e o AASLD recommenda-tions, cTACE is no loner rearded as the standardtreatment o intermediate stae, bein comarableto cTAE. However, new selective techniques, such asTAE with small articles, TACE with DEB or ultrase-lective TACE seem to be more eective obtainin anot neliible rate o comlete resonses, and avoid-in the damae o nonneolastic tissue. In advancedHCC with reserved liver unction soraenib ma beconsidered as a alliative treatment.

OpERATIVE OpTIONS ARE STILL NEEDEDIN HCC

Desite emhasizin the role o ablative treatment ootentiall curable HCC, HR and LT remain as thebasic treatment modalities in certain indications.

Liver resection. It is reasonable that with surveil-lance rorams RFA is the mainsta in areas with ahih revalence o HCC associated to viral heatitis.Elsewhere most o tumours are ound in a smto-matic hase and quite oten in a non-cirrhotic liver aswell. In these cases HR can still be rearded as the

old standard when easible. Without aressivetreatment o these atients with the best suortivecare the median survival is less than 1 ear (28).

As a result o advances in surical techniques anderi-oerative manaement the hosital mortalitater HR is racticall zero and morbidit less than20% when resectin livers o health or Child A cir-rhotic atients in exerienced centres (29). Similar5-ear survival has been seen reardless the atienthad cirrhosis or not but disease-ree survival is de-creased in cirrhotic atients (30). Tolerance to HR de-ends, however, on the deree o imaired liver unc-tion and ortal hertension. I the atient has si-nicant ortal hertension 5-ear survival is onl

25% comared to 74% in atients without ortal h-ertension and with normal bilirubin level (31).One o the advantaes o HR over RFA suested

has been a better contol o micrometastases with ana-tomic resections. A lare Jaanese stud on 72.744atients with a sinle HCC showed an imroveddisease-ree survival ater an anatomical subsemen-tectom than ater non-anatomical minor heatec-tom but onl when the tumour size was between2 cm and 5 cm (32). In conruence, in the consensusstatement or the treatment o HCC the Jaanese So-ciet o Heatolo (JSH) reserved HR to tumoursmore than 3 cm in diameter and 3 or less in numberin atients with Child A cirrhosis (33). HR was also


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rearded as an alternative to RFA in smaller tu-mours.

Sinicant risk actors or earl recurrence are tu-mour ruture, venous invasion and cirrhosis, whereasviral relication in viral heatitis and multile tu-mours increase the risk or late recurrence (34,35).Controvers exists related to the surical marin asHCC seldom recurs to the resection surace (36,37).Nevertheless, it is hihl recommended that the tu-mour should not be exosed durin the surer.

Vascular invasion is a ronostic indicator o HCCdesite the treatment modalit and its risk is hih intumours more than 5 cm in diameter (38). Neither HRnor LT are usuall recommended when vascular in-vasion has been established. However, when easibleHR is the onl alternative o a lare HCC withoutroven dissemination (Fi. 2).

Liver transplantation. Excellent results ater LT us-in Milan criteria rom the stud b Mazzaerro havebeen reroduced multile times b other researchers,and the results seem to be robust and valid acrossdierent oulations and etioloic backrounds (39).However, onl a minorit o HCC atients can betreated with LT due to the scarcit o orans available

or translantation and increasin waitin times inmost countries.

Selection criteria. Indeendentl o TNM stae, theresence o vascular invasion is a determinin a-rameter or aressive disease and recurrence ollow-in LT or HR, but this actor can onl be assessed onhistolo and is thus not available or reoerativeevaluation (40). TNM stae 2 (T2) comrises the Mi-lan criteria. The ronosis o atients exceedin theselimitations is more unredictable, and the Milan cri-

teria can in this sense be viewed as a surroate markeror absence o vascular invasion. Another ronos-tic actor o sinicance is alha-etorotein (AFp).AFp level hiher than 400 /l is a sin o either a-ressive and/or advanced disease (40). The roblemin a oulation settin, however, is that AFp levelsare not sensitive and secic enouh to be o truestain value, whereas it can be o sinicance in thejudement o an individual atient (40).

In a cohort stud o multile centres, the imact ostain on ost exlant atholo (diameter o lar-est tumour, number o nodules and vascular inva-sion) survival was exlored and correlated to osttranslant survival and recurrence (41). The results

A B

C DFi. 2. A and B reresent a lare heatocellular carcinoma (HCC) with a ood ronosis ater riht lobectom. C and D: Child B cirrho-sis with a 3 cm HCC and a susected satellite nodus less than 1 cm in the riht lobe. Liver translantation was the onl otion availableor the atient.


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show that the diameter o the larest tumour is amore imortant redictor or survival and recurrencethan the number o nodules (Fi. 2). Furthermore, asubrou o atients where the sum o the diametero the larest tumour and the total number o noduleswere equal to seven, (u to seven criteria), dis-laed a survival benet that was not sinicantldierent rom those within the Milan criteria. An-other aroach to tumour morholoic criteria hasbeen total tumour volume (TTV). This has the advan-tae o excludin the number o nodules which are oless sinicance than size. TTV o less than 115 cm3has roven to rovide similar results as the Milancriteria (35, 42).

Transplantation beyond the Milan criteria. The con-cet o limitin translantation to BCLC A atients isinherentl linked to the scarcit o liver rats avail-able. Due to the unredictable availabilit, dierentwaitin times and local or national uidelines o theLT indications with resect to tumour size and staesvar.

In eneral, the outcome ater LT or HCC should

ideall be comarable to translantation or beninindications. I translants are erormed outside theestablished criteria, this should not lead to extendedwaitin times or exclusion o other atients. In coun-tries where the Model or End-Stae Liver Disease(MELD) is used or liver allocation, HCC atientswithin the Milan criteria are ranted extra oints toensure access to translantation within reasonabletime.

In the Asian countries, the availabilit o deceaseddonor rats is ver low or absent. Hence, the major-it o rats are derived rom a livin donor. In livindonation, the question o excludin other reciientsrom the access to LT becomes irrelevant. Livin do-

nation enables the waitin times to be short andmiht also encourae translantation o atients onextended criteria.

In Scandinavia, LT or HCC comrises 7.9% o alltranslants erormed, refectin a low incidence othe disease. Concomitantl, the waitin times in theNordic countries are in international comarisonshort, articularl in Norwa, Finland and Sweden,and somewhat loner in Denmark (43). Aarentlthis act miht have an imact on the LT indications.The overall ve-ear survival or LT or HCC in theNordic countries is 57.4%, indicatin that a roor-tion translants are most likel done on extendedcriteria (43). Is this an accetable outcome in LT? The

survival data rom reistries like the Nordic LiverTranslant Reistr (NLTR) or the Euroean LiverTranslant Reistr (ELTR) indicate that LTs in caseswith the actual 5 ear survival o about 50%, such asreLT or heatitis C are still erormed (43, 44).

Translantation on extended criteria does, how-ever, raise certain issues o concern. patients withmore advanced disease have an increased risk odroout on the waitin list, articularl when thewaitin times exceed more than 100 das (31). Con-versel, ver short waitin times miht reclude thenatural selection rocess and lead to translantationo oor candidates that have a ver hih likelihoodo recurrence and short ost translant survival (45).

This miht be o articular relevance in livin donortranslantation, and increased recurrence rates com-ared to whole rat deceased donor rats have beenreorted in the literature (46).

Strateies such as neoadjuvant treatment or down-stain to imrove outcome in extended criteriatranslantation have been suested. Neoadjuvanttreatments are iven rior to the translant rocedurein order to imrove ost translant outcome, whereasdownstain is a term describin lowerin the a-tients morholoical stae. Bridin, on the otherhand, is a related strate to kee atients that qual-i or translantation able to sta on the waitin listor an extended time, i.e. reventin them rom dro-in out (45).

In all these instances, locoreional theraies RFAor TACE can be utilised (47). There are data available,suestin that the rate o droouts miht be reducedb adotin bridin strateies or T2 tumours wherethe waitin times exceed 6 months (45). Furthermore,some studies suest that the resonse to TACE orRFA as downstain modalities can be utilised as a

selection criteria or translantation in atients out-side Milan (48). It has been roosed that a roerresonse to downstain should be evaluated bboth radiolo (Milan criteria) and reduction in AFplevels (47). Conventional Recist criteria aears to beoorl adated or evaluatin the resonse to TACEand RFA, and new, modied criteria (mRecist mod-ied Recist) have been roosed (49).

Another attemt to imrove survival ater LT inHCC is to modi the immunosuressive reimen.Immunosuression is in itsel associated with anincreased risk o malinanc and miht acilitate tu-mour rowth and metastasis. Anti-rolierativeaents, like the m-Tor inhibitor raamcin, could

ossibl oer an oncoloical benet, articularl inatients outside the Milan criteria (50). A lare ran-domised stud comarin conventional immunosu-ression to raamcin that miht ive a better answerto this question is underwa (51).

HEpATIC RESECTION OR LIVER TRANSpLANTATION?

The excellent results ater LT usin the Milan criteriain HCC atients are imaired with the scarcit oorans as the droout rate ma be u to 30% becauseo roression o the disease durin the waitin time(28). HR has been estimated to ield similar results asLT on the intention-to-treat- basis (52). However, ve-

ear disease-ree survival even ater curative HR osmall HCCs has been onl 2236% (30, 53) and onlon-term the recurrence ma be rearded as almostuniversal. Thus the best lon-term result o a multio-cal HCC could be reached with LT. Nevertheless, LTma have a sinicant role in the treatment o HCConl in countries o low revalence o HCC leavinboth RFA and HR as the treatments o choice in thehih revalence areas. With a close ollow-u recur-rent tumours should be treated activel with RFA.

In addition, there is an evidence that the results oa salvae LT ater HR are not inerior to rimar LTs(54). Accordin to poon et al. almost 80% o atientsrimaril treated with curative HR could later be


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treated with LT (30). A raid recurrence ater HR re-ers to a metastatic disease and late recurrences tometachronic tumours with a better ronosis ater LT(34). In act, earl recurrence within one ear couldbe rearded as a contraindication to LT.

CONCLUSION

Durin the last ears the major infuence on the ro-nosis o HCC in develoed countries has beenachieved b surveillance, earl dianosis, and multi-discilinar treatment o the disease. Ater detectinthe tumour a tareted thera with RFA, HR, TACE,or LT or with their combinations ives the atient thebest chance or survival. Neoadjuvant thera anddownstain strateies as well as novel immunosu-ressive reimens miht be o relevance, but urtherstudies are needed to validate these measures in livertranslantation or HCC.

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Received: December 15, 2010

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