Liver Resection Versus

ANNALS OFSURGERY Vol. 218, No. 2, 145-151 ©) 1993 J. B.Lippincott Company

Liver Resection Versus

Transplantation for Hepatocellular

Carcinoma

in

Cirrhotic Patients

HenriBismuth,M.D., F.A.C.S. (Hon), Laurence Chiche, M.D., Rene Adam, M.D.,

DenisCastaing, M.D., Tom Diamond, M.D., F.R.C.S., and AshleyDennison, M.D.,F.R.C.S. From the HepatobiliarySurgery and LiverTransplant Research Unit, South Paris University Faculty of Medicine, Hopital Paul Brousse, Villejuif, France

Objective

Currently,there is considerable controversy about theplace of transplantationinthe treatment of hepatocellular carcinoma(HCC). This study compared resection to transplantation in cirrhotic patients withHCCin ordertodeterminereasonable indicationsof each treatment.

Summary

Background Data

The usualprocedure isto resectwhenfeasible and to transplant inother cases.

Methods

Three-year survival with and without recurrence was analyzed in 60 patients who underwent resection and 60 who underwent transplantation. Several prognostic factors, such as size, number of nodules, portal thrombus, and histologic form, were studied.

Results

In termsof overall survival rates, resection and transplantation yield the same results (50% vs. 47%, respectively, at3 years). For transplantation, however, the rate for survival without recurrenceisbetter than thatfor resection(46% vs. 27%, respectively; p<0.05). Inthe case of small uninodularorbinodulartumors (< 3 cm), transplantation has much better results than resection(survivalwithout recurrence,83%vs. 18%,respectively; p<0.001).However, itseems that a groupof patients with high risk ofrecurrenceafter transplantation can be determined

(diffuse form, morethantwonodules> 3cm,orpresenceof portalthrombus).

Conclusions

The best indication fortransplantation seems to bepatientswith small and uninodular or binodular tumors; until now, these patients were consideredtobe the best candidatesfor resection. Patients undergoing transplantation for unresectable, large, multinodularordiffuse tumors seem torepresent bad indications fortransplantation. These results could helpdefine reasonable indications fortransplantationin an erawithashortageof livergrafts.

Althoughuntil the late 1970sitwasconsideredtobea

frequency

in recent

years."2

Several treatment

options

tumorrarelydiagnosedortreatedand detected

mainly

at are now

available, including hepatic

arterial chemoem-autopsy in cirrhotic

patients,

hepatocellular carcinoma

bolization, alcoholization, hepatic

resection,

and

trans-(HCC) has been diagnosed and treated with

increasing

plantation.'3 When the tumor has

spread

beyond

the 145

146 Bismuth andOthers

liver, a cureisnotpossibleandonlypalliativetreatment may beoffered. However, when there isnoevidence of extrahepaticdisease,anattemptat cureby complete sur-gical excision is applicable, although there is consider-able controversy regarding the most appropriate treat-mentfor each

particular

case.24

Indeed,

results for he-paticresection, whileinitially promising,appeartohave

deteriorated with time2andincontrastliver

transplanta-tion, initially considered a poor treatment option, has recentlybeenassociated withimproved results.4

Further-more,severaltumorcharacteristics,suchassize,number

ofnodules, and portal venous involvement, have been

identifiedasimportant prognostic indicators,but the ex-actsignificanceofthese intermsofdecidingwhich

thera-peutic option is

appropriate

remainstobedetermined.5

In this study, recurrenceandsurvivalratesafter

hepatic

resection or

transplantation

for HCC in cirrhotic

pa-tientswereanalyzed inan attempttodetermine the

ex-act importance of various tumor characteristics and whetherthesearereliableparametersthat could

identify

the mostappropriate surgical option in each particular

case. Resection (N=60) Etiology Alcoholic Posthepatitic Others Classification ofcirrhosis A B C Tumorasymptomatic Size(cm) <3 3-5 5-10 > 10 No.ofnodules 1 2 23

Portal thrombosis-mainbranch

23 (38%) 34(57%) 3(5%) 46 (77%) 13 (21%) 1 (2%) 45(75%) 25 (42%) 21(35%) 14(23%) 50(83%) 10 (17%) 3(5%) Transplantation (N=60) 6 (10%) 44(73%) 10(17%) 19(32%) 21 (35%) 20 (33%) 49(82%) 28 (47%) 17(28%) 13 (22%) 2 (3%) 24(40%) 6(10%) 30(50%) 10 (17%)

PATIENTS

AND

METHODS

Patients

From January 1980 to June 1991, 178

patients

with HCC underwent liver resection or

transplantation

at

Hopital

Paul Brousse,

Villejuif,

France. Thetumor was

presentinanoncirrhotic liver in52 cases

(42

resections and 10

transplantations)

and in acirrhotic liver in 126 cases (60 resections and 66

transplantations).

In six

cases, an HCC was discovered in a cirrhotic liver after

hepatectomy and liver

transplantation

for

end-stage

liverdisease.These cases were excluded because the aim

of thestudywas to compareresection and

transplanta-tion for known tumors and the

prognosis

for these

tu-morsdiscovered aftertotalhepatectomyand

transplan-tation may be more favorable because theyare

usually

less than 2 cm indiameter.6 Thus, 120casesofHCC ina

cirrhotic liverwereavailable forstudy.The

diagnosis

of cirrhosis was confirmed

histologically

in each case, as wasthatofHCC. Otherprimaryhepaticcancerssuch as

hepatoblastoma, hemangio-epithelioma, or

cholangio-carcinomawere excluded. Therewere no casesof fibro-lamellarcarcinoma.

Patientdetailsincluding etiologyofcirrhosis, severity of cirrhosis accordingtothe Paul Brousse classification

(which is amodification of the Child-Pughscoring

sys-tem),7

presence ofsymptoms and tumorcharacteristics

(including sizeand numberof nodules[Nakashima

clas-sification8]),

and presenceorabsenceof

portal

thrombo-sis are

given

in Table 1. Most

patients

did not have

symptomsattributabletotheirtumor(75%inthe

resec-tiongroupand 82% in the

transplantation group).

Inthe

resectiongroup, 42%ofthe tumors were less than 3 cm; in thetransplantationgroup, 47%ofthe tumors were less than 3 cm. The

major

differences between the two groups were the severity ofthecirrhosis (77% grade A and 2%gradeCintheresectiongroupcomparedto32%

grade A and 33% grade C in thetransplantationgroup) and the numberof nodules(a single nodule in 83% ofthe

resectiongroupcomparedto 30% of thetransplantation group).

Preoperative Investigation

Preoperative investigations included hepatic

ultra-sound, abdominal and thoracic computerized

tomo-graphic (CT) scans, bone scintigraphy, and sequential serum alpha-feto proteinmeasurements. Inthe latter 2 years ofthe series, hepatic arterial chemoembolization

was performed before resection or

transplantation.3

In

patients undergoing resection,this was performedboth toreduce the tumor mass and to detect additional nod-ules(demonstrated duringtheprocedure or on a comput-erizedtomographicscanperformed 3 weeks later by the

persistence oflipiodol within the nodule). In patients

undergoing transplantation, it was performed as

adju-Address reprint requests to Henri Bismuth, M.D., F.A.C.S. (Hon), HopitalPaulBrousse,Villejuif94800, France.

Resection VersusTransplantationfor HCC 147

vanttherapy while waiting for a suitable graft (except in the case of severe liverinsufficiency).

Resection

Techniques

In each case, a standardized, systematic examination oftheabdominal cavitywasperformedtoexclude

perito-neal metastases.Hepatic pedicleandceliac lymphnodes, if present, were removed for frozen section histologic examination. If this waspositive, resectionwasnot

per-formed.Systematic, intraoperative hepatic

ultrasonogra-phy wasperformedtodetectadditionalnodules or portal

thrombosis. Ifadditional nodules were detected,

ultra-sound-guidedneedlebiopsywasperformed;if morethan twohistologically positivenodules were identified, liver resection was notperformed.

The resection techniques principally involved

ultra-sound-guided segmentectomy or

sub-segmentectomy.9"10

Assessmentof liver function beforesurgery by measure-mentof routine liver function tests(including

coagula-tionstatus)andindocyaninegreenclearance was used to

indicatethe extent ofparenchymalresectionthat could be safely performed. After resection, adjuvant

chemo-therapywas notgiven because of underlying cirrhosis.

Transplantation Technique

A systematic

examination

ofthe abdominal cavity

wasperformedin each case(including frozen section his-tology) todetect

extrahepatic

disease. In the eventofa

positive

result,analternative

patient

with

nonmalignant

disease was immediately prepared to receive the

graft.

Thetechnique fortransplantationwasthestandardone used inour

unit,"

withseveral modificationsduetothe presenceofmalignant disease.The useofacell saver was

avoided iftumor waspresentatthesurface ofthe

liver,

andextracorporeal bypasswasusedonly after

clamping

oftheportal veinin ordertoavoid

dislodging

small

in-trahepatic

portalthrombi

during aspiration

of the

portal

trunk. Thepresence ofa portal thrombus

invading

the

portal trunk(butnotthebifurcationor

primary

and

sec-ondary branches) wasconsidered acontraindicationto

transplantation.

After

transplantation,

routine

triple

im-munosuppression with

azathioprine,

cyclosporine,

and

steroids was used.'2

Postoperative chemotherapy

con-sisting

of doxorubicin

(Adriamycin,

Adria

Laboratories,

Columbus,OH) (50

mg/M2

on

day 1)

and5-fluorouracil (500

mg/M2

ondays2to

5)

given

for ninecourses over5 days each month foratotal of 9 monthswasstartedas

soonasthepatientcould tolerateit.

Histologic

Study

Inall cases,tumoraland nontumoral liverwas

exam-ined.Thesizeofthe tumor, thenumber of

nodules,

and

thepresence of capsule, satellites nodules,and vascular

invasionwerenoted. The tumor wasclassifiedaccording totheNakashima classification.8Intheresection group, all tumors except one (a diffuse type that was trans-planted 6 months later) wereexpansive type (one or two nodules). In thetransplantation group, there were 51

ex-pansive (uninodularormultinodular),4infiltrative,and 5diffuse forms.Thewholeliverwassystematically

exam-ined and dysplasia, carcinomatous foci were noted in

cirrhotic nodules.

Follow-up

In all cases of resection or transplantation, patients wereobserved for detection of recurrence by alpha-feto

protein dosage and ultrasound of the liver every 3 to 4

months,andperiodic computerizedtomography scan of the lungs andbone scintiscan.

Statistical Analysis

Comparison of survival and survival without recur-rence rates in each group, in relation to the tumor size and number ofnodules, was performed using the

Ka-plan-Meiermethod and the log-rank test.

RESULTS

Morbidity and Mortality

Postoperative complications occurred in 24 patients

(40%) of the resection group. These included hemor-rhage requiring repeat laparotomy,4 bile fistula that closed

spontaneously,2

ascitesthat regressed

spontane-ously,"

liver failure with ascites,andrenal

dysfunction.'3

In the transplantation group, postoperative surgical

complications

occurred inninepatients (15%).These in-cluded postoperative hemorrhage,3 intestinal

perfora-tion,2

thrombosis ofthehepatic

artery,'

infected

ascites,'

biliary

stricture,' and wound

abscess.'

Intheresectiongroup,there weresixoperative (within

2 months) deaths(10%). These were caused by hepatic

failure,3

unexplained

cardiac

arrest,' sepsis,'

and

hemor-rhage.'

In the transplantation group, there were three deaths(5%), all causedby cardiac complications.

Survival

Resultsforoverallsurvivalandsurvivalwithout recur-renceare shown inFigures 1 and 2 and Table 2. Inthe

resectiongroup, theoverall3-year survivalrate was52%,

butmostof these

patients

hadrecurrentdisease

(survival

without recurrence, 27%). Inthetransplantationgroup, the overall 3-year survival rate was 49%;

however,

in Vol.218 -No. 2

148 Bismuth and Others UECflON(60paias)w _ ofOWN mvlv 6 12 18 24 30 ofoven TRANWNAT1ON(60pa§uW so 6o 40 20 36 months 6 12 18 24 30 36 minaim s0 0 40 20

survival rate at 2 years). In the otherpatients, carcinoma-tous foci incirrhotic nodulesor degenerated adenoma-tous hyperplasia was discovered in theparenchyma far from thetumorin 24% of thecases.

Tumor

Size

Theinfluence oftumorsize onsurvivalin each group is shown inFigure 1 and Table 2. Inthe resectiongroup, the3-yearsurvivalrateforpatientswithtumorsless than 3cm was39%(survival without recurrence, 18%),while for those withlesions greater than 3cmitwas56% (sur-vival without recurrence, 32%). In the transplantation

group,the 3-yearsurvival rateforpatients withtumors less than 3 cm was 60% (survival without recurrence,

RESECTION(60patients) TRANSPLANTATION(60patients)

% of urvlval withoutreerence

inn . ao s0 40 20 6 12 18 24 30 36 8 12 18 24 30 36 months months askige Amultipe

Figure 1. Overallsurvival in resection andtransplantationgroups.Upper

curves-overall results. Middlecurves-influenceof the numberof nod-ules(multiple-morethanone). Lowercurves-influence oftumorsize.

contrast to the resection group, most ofthese patients

were free fromrecurrence (survival without recurrence,

46%).Of47patientsobservedformorethan3 yearsafter resection,33died(18 ofthe 28 knowncauses were

attrib-utedtorecurrence),5arealive withrecurrence,and 9are

alivewithout demonstrable disease

(including

1

patient

who underwentre-resection and 3patientswholater un-derwent transplantation). Of22 patients in the

trans-plantationgroupwho have beenobservedfor more than 3 years, 10have died (5 of recurrence) and 12 are alive without recurrence.

Histology

In the transplantation group, all patients who had a diffuse HCC died of recurrence at 8 to 20 months (0%

6 12 16 24303276

d 12 18 24 30 30 months

S ofsurvivalwifoutrecrrence

% of urvivalwithoutrecurrnce

1.- . 4 A ao 60 40 20 1216 24 3036 6 12 1 243036

Figure 2. Survival withoutrecurrence in resection and transplantation

groups. Upper curves-overall results. Middle curves-influence of the number ofnodules(multiple-more thanone). Lower curves-influence oftumor size. 521 491 so 60 40 20 so 60 40 20 *< 3cm 3e-5cm A>S cm al survival 00Rl_ 63% 461 511 461

60

60 40 468 20 6 12 18 24 30 36 months O< 3C o3-6 cm a> cm 6o 60 40 20 261 201 491 42%

Ann.Surg.-August1993

Resection VersusTransplantation forHCC 149 Resection Transplantation (N = 60) (N =60) Total series 52% NS 49% (27%) p < 0.05 (46%) Size (cm) < 3 39% NS 60% (18%) p < 0.05 (56%) 23 56% NS 43% (32%) NS (39%) No. of nodules Single 53% NS 46% (28%) (20%) Multiple (> 1) 46% NS 51% (20%) p < 0.05 (49%) Size and number

< 3 cm + 1 or 41% p < 0.05 83%

2 nodules (18%) p < 0.001 (83%)

3 cm + 3 or - 46% p < 0.01

more nodules (44%)

56%; p = 0.03 comparedto the resection group), while

forthose withtumors greaterthan 3cmitwas43%

(sur-vival withoutrecurrence, 39%).

Number of

Nodules

Theinfluence of the number of nodulesonsurvival in

each group is shown in Figure 1 and Table 2. In the

resectiongroup,the3-year survivalrateforpatients with

onenodulewas53%(survival withoutrecurrence,28%),

whilefor those with multiple (more than one) nodules it

was 46% (survival without recurrence, 20%). In the

transplantation group, the 3-year survival rate for

pa-tients with a single nodule was 46% (survival without

recurrence, 41%). For patients with multiple nodules,

the 3-year survival rate after transplantation was 51% (survival withoutrecurrence,49%;p=0.04comparedto

the resectiongroup).

Influence

of Tumor Size and Number of

Nodules

(Table 2)

Whentumorsizeand number of noduleswere consid-eredtogether,survival(83%)and survival without recur-rence (83%)werebetter aftertransplantationthan after

resection inpatientswithtumorsless than3cmandone ortwo nodules(3-yearsurvivalrate,41%;p= 0.05;

sur-vivalwithoutrecurrence, 18%;p=0.001).The results of

transplantationin this group ofsmall,uninodularor bi-nodular tumors were better than those in patientswith tumors morethan 3 cm and three ormore nodules

(3-year survival rate,49%;p= 0.03; survival without recur-rence, 44%;p <0.01).

Portal

Thrombosis in a Main Branch

In the resection group, all 3 patients with a tumoral thrombus in a mainbranch had a recurrence at 9, 36,

and60 months; 2 died at 45 and 64 months and 1 isalive

after livertransplantation.

Inthetransplantationgroup, theexistence of a portal thrombosis in a main branch (ten patients) was signifi-cantlyassociated with a worseprognosis(survival rate at 3years withportalthrombosiswas 20% vs. 55% without portalthrombosis;p = 0.001).

DISCUSSION

The diagnosisand treatment of HCC has progressed remarkably in the last 10 to 15 years. These advances have been due largely to improved diagnostic imaging andtheapplication of sophisticatedsurgical techniques,

including liver

transplantation.'

Ofthe treatment op-tions now available (alcoholization, chemoemboliza-tion, hepatic resection, and hepatic transplantation), only resection and transplantation, bytheoretically

re-movingall tumor tissue, can offerthe chance of long-term survival or cure. While both ofthese have been

appliedwith varyingresults in recent years,itisnotyet

possibletosay which providesthe betteroptionin each

individual case. This is furthercomplicated by the fact

that reported series generally concern all types of pri-mary hepatic malignancy and both cirrhotic and

non-cirrhotic patients.4"3"4 This may lead to confusing re-sultsbecausethenaturalhistory ofthedisease,the

surgi-cal management, and the outcome aredifferent in each

case.'

Thus,in thisstudy,wehave concentrated on resec-tion and transplantation for HCCin cirrhotic patients only (in whom it isthe most frequent type ofprimary hepatic malignancy) in order to reduce the number of

variablesand allow amorepreciseanalysis and

interpre-tation of results.

Clearly,whenthere isextrahepatic disease, neither re-section nor transplantation will curethe patient. A re-centautopsy studyby Yukietal.'5 showed that the fre-quencyofextrahepatic diseaseishighandincreases with tumorsize, histologictype, and numberof nodules. The incidence of hematogenous extrahepatic metastasis ranged from 14% forsingle nodulesto 82% for

diffuse,

multinodular disease. Experience with transplantation

in ourseries wouldseem to confirm this because even whenthoroughpreoperativeandperoperative screening

150 Bismuth and Others

is negative, there is a high rate of recurrence, which is often dramatic andearly.Thisstronglysupports the con-cept ofmicroscopicextrahepatic spreadand the

contri-bution ofthe immunosuppressive effect of both major

surgeryandadjuvant immunosuppressive regimens.

If there is noextrahepaticspread, resection may cure thepatient, providingthefollowingcriteriaarefulfilled.

First, a radical resection with at least a 1-cm clearance mustbeobtained.'6 Second, it is essential that thereare no coexistent undetected daughter nodules present in the liver(eventhemostthorough peroperative screening oftheliverby ultrasound can miss nodules less than 1 cm).Third, theremustbeno newdevelopmentof HCC in the remaining cirrhotic liver. Even in theabsence of

multinodulardisease,newtumors,provedtobe different from the original by DNA studies,'7 may appear in the

liversoonafterresection. Itseemsthat these criteriaare rarely fulfilled in Western countries; this is reflected in our results for

resection,

with a

3-year

survival rateof 50% and a 3-year survival without recurrence rate of

only 23%. Although there was no

significant

difference insurvivalafter resectionbetween

patients

withone nod-ule andthosewith morethanone

nodule,

the influence

of lesion size was unexpected and

puzzling.

While it seems reasonable to expect results to be better for

pa-tients with small (< 3 cm)

lesions,

the

opposite

was

found-better survival rates for

patients

with lesions greater than 5 cm. How can this apparent paradox be

explained?

One could postulate that when resection is

performed in a patient with one or two small nodules

discovered byrepeated

screening,

otherundetected nod-ules may be present. Our study oftheparenchyma in cases of

transplantation

for

expansive

form seems to

confirmthe

frequent

existence ofundetected

carcinoma-tousfociin cirrhotic liver

(24%).

Incontrast, whenresectionofasingle, largenoduleis performed, the chance that the lesion is truly

solitary

may be higher, hence possibly explainingthe better re-sultsafterresectionin thesepatients.

This,

together with differencesin thebiology ofthediseaseand the underly-ing cirrhosis, mayalso helpexplainthedifferent survival

ratesbetween our series and those from the Far East. For

lesions less than 5 cm, 5-year survival rates of43% in

Japanand 75% inChina have been reported, compared tothe3-year survival rateof 50% in our

series.2"8

Fur-thermore,in contrasttothefrequentearlyrecurrencein ourseries,recurrenceseems tobefrequentbut latein the

Japanese series2 and markedly low in the Chinese

se-ries.18

This concept may also explain why transplantation, whencompared to resection in similar patients (tumors

<3cmand one or twonodules),is associated with better resultsbecause by removingthe liver completely the risk ofsynchronous nodules ormetachronous nodules is

re-moved. In contrast, when performed for tumors more than 3 cm and three or more nodules, the tumor may have already spread outside the

liver,'5

explainingthe poorer results aftertransplantation in this group.

Recently, the commonly adoptedattitudehas been to resecttumors that can.be resected and toperform trans-plantation for those that could

not.4"4"'9

The generally poor results fortransplantation in recent series reported by Ismail et al.(0% survival rate at 1 year)'9andRingeet al. (17% survival rate at 5 years)'4 can nowpossibly be explained by the findings of our study, which suggest that inclusion oflarge lesions, with the comparatively poorer results forthese, adverselyaffects the overall re-sults fortransplantation. Therefore, itseemsreasonable to suggestthat, in Westerncountries, transplantation is

particularly recommended for the group ofpatientsin whichit achievesthe best results (i.e., thosewithtumors less than 3 cm and one or twonodules).

Althoughtransplantationstillseems tobe abetter op-tion thanresection for largetumors,the resultsfor

trans-plantation arepoor, witha3-year survival rateof 31%. This iscomparable to thefigures for transplantation for secondary livertumorsorhilarcholangiocarcinoma.'3'20

As in these latter groups, the general consensus is currently against transplantation, with the shortage of donor livers. Perhaps a similar attitude should be

adopted fortheunfavorableforms ofHCC: tumors more than 3cmand three ormorenodules,tumorswithportal

thrombosis in amain branch,ordiffusetumors. Should resection be abandoned completely in the treatmentofHCC? Itis certainthat some casesofsmall HCC will belocalizedandwillremainso, asseems to be the case in the series from China.'8 Thesepatientsmay be curedbyhepatic resection. Effortsmust,therefore,be made toidentifythese cases in Westerncountriesso that

resection is notwithheld from suitablecases and

trans-plantation is not performed unnecessarily. Resection

stillisprobablyindicated fortumors morethan3 cm, as asecond stage procedureaftertumorreductionby adju-vanttherapy such aschemoembolization.3In afew cases

of large tumors, transplantation may be indicated if,

after

adjuvant

therapy, thereisadramatic reductionin thesize ofthe tumor and thereisnoevidenceof

extrahe-patic spread.

We believe that hepatic transplantation for HCC should beavoided forlarge (> 3 cm)lesions with three or more nodules and should be restricted to small lesions

(<3cm)with one or two nodules, the group which until nowwas thought to be the most suitable for resection. Resection may still be indicated for some small tumors that tend to remain localized (as in the series from the FarEast), andfurther attempts must be made in Western countries to identify these types of lesions. Resection may be appropriate for patients with large lesions after Ann.Surg.*August1993

Resection VersusTransplantation for HCC 151

reduction ofthetumor mass by chemoembolizationor other adjuvant therapy. Transplantation may also be

consideredforthesepatients,dependingonthedegreeof priority given to HCC as an indication (compared to otherindications)fortransplantation.

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