Management of Hepatocellular Carcinoma.pdf

AASLD PRACTICE GUIDELINE

Management of Hepatocellular Carcinoma

Jordi Bruix 1 and Morris Sherman 2

Preamble

These recommendations provide a data-supported ap-

proach to the diagnosis, staging and treatment of patients

diagnosed with hepatocellular carcinoma (HCC). They

are based on the following: (a) formal review and analysis

of the recently-published world literature on the topic

(Medline search through early 2005); (b) American Col-

lege of Physicians Manual for Assessing Health Practices

and Designing Practice Guidelines. 1 (c) guideline poli-

cies, including the AASLD Policy on the Development

and Use of Practice Guidelines and the AGA Policy State-

ment on Guidelines 2 ; (d) the experience of the authors in

the speciﬁed topic. We have also reviewed the guidelines

prepared at the time of the Monothematic Conference of

the European Association for the Study of the Liver

(EASL) 3 and the practice of authors experienced in the

ﬁeld. Intended for use by physicians, these recommenda-

tions suggest preferred approaches to the diagnostic, ther-

apeutic, and preventive aspects of care. They are intended

to be ﬂexible, in contrast to standards of care, which are

inﬂexible policies to be followed in every case. Speciﬁc

recommendations are based on relevant published infor-

mation. In an attempt to characterize the quality of evi-

dence supporting recommendations, the Practice

Guidelines Committee of the AASLD requires a category

to be assigned and reported with each recommendation

(Table 1). These recommendations are fully endorsed by

the American Association for the Study of Liver Diseases.

care of patients with HCC has been undertaken by hepa-

tobiliary surgeons, interventional radiologists, and on-

cologists. Hepatologists in North America are not trained

to perform the procedures required to treat HCC, such as

alcohol injection, radiofrequency ablation, or hepatic ar-

tery catheterization, although hepatologists in Japan and

elsewhere may perform many of these procedures. As a

result, the role of the hepatologist traditionally has been

limited to making the diagnosis and providing care of the

underlying liver disease. However, more recently, the role

of the hepatologist has changed. First, in many centers the

development of multidisciplinary clinics has emphasized

the role of the hepatologist in assessing the patient’s liver

disease status, and carefully managing the liver disease

before and during treatment. The hepatologist has also

become more actively involved in deciding what form of

therapy is most appropriate and whether the patient’s

liver function would allow that form of therapy to be

given. In addition, arising out of caring for patients with

end stage liver disease, hepatologists also institute surveil-

lance for HCC and manage the investigation of abnormal

results. Finally, hepatologists are involved in the decision

whether or not to offer liver transplantation to patients

with HCC.

There have been many reviews of various aspects of the

care of patients with HCC, but only one clinical practice

guideline has been published in the Western literature.

The European Association for Study of the Liver (EASL)

sponsored a single topic conference on HCC in 2000.

The proceedings of this conference were published in

2001. 3 This document largely reﬂected practices in Eu-

rope, and possibly North America, whereas practices in

Japan are somewhat different.

Introduction

Over the last 5 to 8 years evidence has been accumu-

lating in different countries that the incidence of hepato-

cellular carcinoma (HCC) is rising. 4-9 Traditionally, the

Abbreviaitons: CLT, Cadaveric liver transplantation; LDLT, live donor liver

transplantation; PEI, Percutanoeus ethanol injection; RF, radiofrequency; TACE,

Transarterial chemoembolization; PS, Performance Status.

From the 1 BCLC Group. Liver Unit. Hospital Cl´nic, University of Barcelona.

Institut d’Investigacions Biom`diques August Pi i Sunyer, Barcelona, Spain; and

2 University of Toronto and University Health Network, Toronto, Canada.

Both authors contributed equally to this work.

Address reprint requests to: Dr. Jordi Bruix, Liver Unit, BCLC Group Hospital

Clinic, Barcelona, Spain 08036. E-mail: bruix@ub.edu; fax: (34) 93-227-5792

Published online in Wiley InterScience (www.interscience.wiley.com).

DOI 10.1002/hep.20933

Potential conﬂict of interest: Nothing to report.

Surveillance for Hepatocellular Carcinoma

Deﬁnitions of the terms used in this section are given

in Table 2.

Surveillance for HCC involves more than simply ap-

plying a screening test or tests. Surveillance should be

offered in the setting of a program or a process in which

screening tests and recall procedures have been standard-

ized and in which quality control procedures are in place.

The process of surveillance also involves deciding what

level of risk of HCC is high enough to trigger surveillance,

what screening tests to apply and how frequently (surveil-

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HEPATOLOGY, Vol. 42, No. 5, 2005

BRUIX AND SHERMAN 1209

lance interval), and how abnormal results should be dealt

with (diagnosis and/or recall).

Surveillance for HCC has become widely applied de-

spite, until recently, the absence of evidence of beneﬁt.

There is a single randomized controlled trial of surveil-

lance versus no surveillance that has shown a survival ben-

eﬁt to a strategy of 6-monthly surveillance with

alphafetoprotein (AFP) and ultrasound. 10 This study,

which was performed in China, recruited 18,816 patients

who had markers of current or prior hepatitis B infection.

Adherence to surveillance was suboptimal (less than 60%)

but in the subjects in the surveillance arm the HCC re-

lated mortality was reduced by 37%. These results prob-

ably represent the minimum beneﬁt that can be expected

from surveillance, because of poor compliance. In con-

trast, an earlier study, also conducted in China failed to

show beneﬁt, largely because patients who were diagnosed

with HCC did not undergo appropriate treatment. 11 Ide-

ally, these results should be validated in other geographi-

cal areas and therefore, additional randomized controlled

trials (RCT) assessing the beneﬁts of surveillance are still

considered necessary. Such trials would be difﬁcult to

undertake, but are essential to unequivocally determine

the beneﬁt of surveillance in reducing HCC mortality.

The objective of HCC surveillance must be to decrease

mortality from the disease. Fewer people should die from

HCC, or if this is not possible, surveillance should at a

minimum provide a meaningful improvement in survival

duration. Other endpoints, such as stage migration (de-

tecting earlier disease) and 5-year mortality rates are not

appropriate surrogate endpoints. This has clearly been

shown by analysis of the Surveillance, Epidemiology and

End Results (SEER) Program of the National Cancer In-

stitute (NCI), which demonstrated that these endpoints

did not correlate with a reduction in disease-speciﬁc mor-

tality. 12

There are several sources of bias to be considered in

assessing reports of surveillance studies, such as lead-time

bias and length bias. Only a RCT can eliminate these

biases completely. Several studies have shown that surveil-

lance does detect earlier disease (stage migration). 13–16

However, as discussed above, this does not correlate well

with reduction in disease-speciﬁc mortality. Uncontrolled

Table 2. Deﬁnitions

Screening—application of diagnostic tests in patients at risk for HCC, but in

whom there is no a priori reason to suspect that HCC is present.

Surveillance—the repeated application of screening tests.

Enhanced follow-up—the series of investigations required to conﬁrm of refute a

diagnosis of HCC in patients in whom a surveillance test result is abnormal.

In addition to the use of additional diagnostic tests the interval between

assessments is shorter than for surveillance since there is a concern that a

cancer already exists.

Lead-time bias—This is the apparent improved survival that comes from the

diagnosis being made earlier in the course of a disease than when the

disease is diagnosed because of the development of symptoms. Unless

properly controlled, studies of surveillance will show enhanced survival

simply because the cancer is diagnosed at an earlier stage.

Length bias—This is the apparent improvement in survival that occurs because

surveillance preferentially detects slow growing cancers. More rapidly growing

cancers may grow too large to be treated between screening visits

studies, all subject to lead-time bias, have suggested that

survival is improved after surveillance. 13,16

Surveillance for HCC is widely practiced and can gen-

erally be recommended for certain at-risk groups. HCC

detected after the onset of symptoms has a dismal prog-

nosis (0%-10% 5-year survival). 17 In contrast, small

HCCs can be cured with an appreciable frequency. 17–21

Five-year disease-free survival exceeding 50% has been

reported for both resection and liver transplanta-

tion. 17,22-30 Patients surviving free of disease for this du-

ration must be considered cured. For these patients it is

highly likely that surveillance did indeed decrease mortal-

ity. Since major advances in our ability to treat HCC are

less likely to come from treating late stage disease it is

therefore important to ﬁnd early stage disease.

Deﬁnition of the At-Risk Population

The decision to enter a patient into a surveillance pro-

gram is determined by the level of risk for HCC. This, in

turn, is related to the incidence of HCC, and it is inci-

dence that most people use to assess risk. However, there

are no experimental data to indicate what level of risk or

what incidence of HCC should trigger surveillance. In-

stead, decision analysis has been used to provide some

guidelines as to the incidence of HCC at which surveil-

lance may become effective. An intervention is considered

effective if it provides an increase in longevity of about

100 days, i.e. , about 3 months. 31 Although the levels were

set years ago, and may not be appropriate today, interven-

tions that can be achieved at a cost of less than about

$50,000/year of life gained are considered cost-effec-

tive. 32 There are now several published decision analysis/

cost-efﬁcacy models for HCC surveillance. The models

differ in the nature of the theoretical population being

analyzed, and in the intervention being applied. Nonethe-

Table 1. Levels of Evidence According to Study Design

Grade

Deﬁnition

Randomized controlled trials

II-1

Controlled trials without randomization

II-2

Cohort or case-control analytic studies

II-3

Multiple time series, dramatic uncontrolled experiments

III

Opinion of respected authorities, descriptive epidemiology

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HEPATOLOGY, November 2005

Table 3. Surveillance Is Recommended for the Follow

Groups of Patients (Level III)

carriers without cirrhosis. These patients, particularly in

Asia and Africa, are also at risk for HCC. A cost-efﬁcacy

analysis of surveillance of hepatitis B carriers using ultra-

sound and AFP levels suggested that surveillance became

cost-effective once the incidence of HCC exceeded 0.2%/

year (Collier J and Sherman M, unpublished observa-

tions). The subgroups of hepatitis B carriers in which the

incidence of HCC exceeds 0.2%/year are given in Table

3. These groups are discussed in more detail below.

Hepatitis B carriers

Asian males 40 years

Asian females 50 years

All cirrhotic hepatitis B carriers

Family history of HCC

Africans over age 20

For non-cirrhotic hepatitis B carriers not listed above the risk of HCC varies

depending on the severity of the underlying liver disease, and current and

past hepatic inﬂammatory activity. Patients with high HBV DNA

concentrations and those with ongoing hepatic inﬂammatory activity

remain at risk for HCC.

Non-hepatitis B cirrhosis

Hepatitis C

Alcoholic cirrhosis

Genetic hemochromatosis

Primary biliary cirrhosis

Although the following groups have an increased risk of HCC no

recommendations for or against surveillance can be made because a lack

of data precludes an assessment of whether surveillance would be

beneﬁcial.

Alpha1-antitrypsin deﬁciency

Non-alcoholic steatohepatitis

Autoimmune hepatitis

Hepatitis B

Beasley et al., in a prospective controlled study showed

that the annual incidence of HCC in hepatitis B carriers

was 0.5%. 36-38 The annual incidence increased with age,

so that at age 70 the incidence was 1%. The incidence in

patients with known cirrhosis was 2.5%/year. The relative

risk of HCC was about 100, i.e. , hepatitis B carriers were

100 times more likely to develop HCC than the unin-

fected. Sakuma et al. 39 found the incidence of HCC in

male Japanese railway workers was 0.4%/year. Both these

populations were male and Asian, with the hepatitis B

infection likely acquired at birth or in early childhood.

Uncontrolled prospective cohort studies in North Amer-

ica, where the epidemiology of hepatitis B is different, i.e. ,

hepatitis is acquired later in life, have indicated that the

incidence of HCC in HBV carriers varies widely. 40-42

Villeneuve et al. 40 found no tumors in a cohort infected

with HBV and followed for 16 years. McMahon et al. 41

reported an incidence of HCC of 0.26%/year in a study of

HBV-infected individuals in Alaska. Sherman et al. 42 de-

scribed an incidence of 0.46%/year in their cohort. In

Europe HCC in hepatitis B carriers occurs mainly in pa-

tients with established cirrhosis. 43,44 Non- Asian chronic

carriers who are anti-HBe-positive with long-term inac-

tive viral replication and who do not have cirrhosis seem

to have little risk of developing HCC. 45-48 Whether sur-

veillance is worthwhile in this population is not clear.

This is not true for Asian hepatitis B carriers without

cirrhosis, who remain at risk for HCC regardless of repli-

cation status. 45,49-51 Similarly, the risk of HCC persists in

long-term HBV carriers from Asia who lose HBsAg, and

these patients should continue to undergo surveillance. 52

In Caucasian hepatitis B carriers who lose surface antigen

the risk of HCC seems to decline dramatically. 53,54

The annual incidence of HCC in male hepatitis B car-

riers from South East Asia only starts to exceed 0.2% at

about age 40 38 irrespective of presence of cirrhosis or dis-

ease activity. In contrast, in Caucasians the risk is related

to inﬂammatory activity and the presence of cirrhosis.

Therefore Asian men should undergo surveillance from

age 40 onwards. HCC will occur in younger patients, but

less, these models have several results in common. They

all ﬁnd that surveillance is cost-effective, although in some

cases only marginally so, and most ﬁnd that the efﬁcacy of

surveillance is highly dependent on the incidence of

HCC. For example, Sarasin et al. 33 studied a theoretical

cohort of patients with Child–Pugh A cirrhosis and found

that if the incidence of HCC was 1.5%/year surveillance

resulted in an increase in longevity of about 3 months.

However, if the incidence of HCC was 6% the increase in

survival was about 9 months. This study did not include

transplantation as a treatment option. Arguedas et al., 34

using a similar analysis which did include liver transplan-

tation in a population of hepatitis C patients with cirrho-

sis and normal liver function, found that surveillance with

either CT scanning alone or CT scanning plus ultrasound

became cost-effective when the incidence of HCC was

more than 1.4%. However, this study has to be inter-

preted cautiously, because the performance characteristics

of CT scanning were derived from diagnostic studies, not

surveillance studies (see Surveillance Tests). Lin et al. 35

found that surveillance with AFP and ultrasound was

cost-effective regardless of HCC incidence. Thus, for pa-

tients with cirrhosis of varying etiologies, surveillance

should be offered when the risk of HCC is 1.5%/year or

greater. Table 3 describes the groups of patients in which

these limits are exceeded. These groups of patients are also

discussed in more detail below.

The above cost-efﬁcacy analyses, which were restricted

to cirrhotic populations, cannot be applied to hepatitis B

HEPATOLOGY, Vol. 42, No. 5, 2005

BRUIX AND SHERMAN 1211

the efﬁcacy of providing surveillance to all carriers

younger than age 40 is likely to be low. The incidence of

HCC in women is lower than in men, although age-

speciﬁc incidence rates are hard to come by. Nonetheless,

it seems appropriate to start surveillance at about age 50 in

Asian women. All hepatitis B carriers with cirrhosis, re-

gardless of age should be screened for HCC. In the pres-

ence of a history of a ﬁrst degree relative with HCC

surveillance should start at a younger age than 40, 55 al-

though what that age should be is hard to deﬁne. Africans

with hepatitis B seem to get HCC at a younger age. 56,57

Expert opinion suggests that surveillance in these popula-

tions should also start at a younger age. Whether this is

true in Blacks born elsewhere is uncertain. In Caucasian

hepatitis B carriers with no cirrhosis and with inactive

hepatitis, as determined by a long term normal ALT and

low HBV DNA concentration 44,46,47,58 the incidence of

HCC is probably too low to make surveillance worth-

while. However, there are additional risk factors that have

to be taken into account, including older age, persistence

of viral replication and co-infection with hepatitis C or

HIV, or the presence of other liver diseases. Nevertheless,

even in the absence of cirrhosis, adult Caucasian patients

with active disease are likely at risk for HCC, and should

be screened.

There have been several attempts to develop non-inva-

sive markers to predict the stage of ﬁbrosis 65-67 and if

properly validated, these could be used to determine when

to initiate surveillance. Similarly, several other markers

may predict a signiﬁcant risk of HCC. One such marker

may be the platelet count. It has been suggested that the

incidence of HCC in hepatitis C cirrhosis only increases

substantially once the platelet count is less than 100 10 9 /

L, 62,68,69 regardless of liver function. This needs to be

validated. Others have attempted to develop predictive

indices based on panels of commonly performed serolog-

ical tests such as alpha 2-macroglobulin, apolipoprotein

A1, haptoglobin, bilirubin and gamma-glutamyl-

transpeptidase and the AST/ALT ratio. 67,70 However,

these indices have still to be validated before entering

general use and cannot be recommended at present.

Co-infection With HIV

Patients who are co-infected with HIV and either hepati-

tis B or hepatitis C may have more rapidly progressive liver

disease 71 and when they reach cirrhosis they are also at in-

creased risk of HCC. 72 The MORTAVIC study indicated

that HCC was responsible for 25% of all liver deaths in the

post-HAART era. 73,74 The criteria for entering co-infected

patients into programs for HCC screening are the same as for

mono-infected patients, i.e. , criteria based on the stage and

grade of liver disease as described above.

Hepatitis C

The risk of HCC in patients with chronic hepatitis C is

highest and has been best studied in patients who have

established cirrhosis, 59-62 in whom the incidence of HCC

is between 2%-8% per year. It should be noted that these

data come from clinic-based studies. There is a single

prospective population-based study of the risk of HCC in

patients with hepatitis C. 63 In this study of 12,008 men

being anti-HCV-positive conferred a 20-fold increased

risk of HCC compared to anti-HCV-negative subjects.

The presence or absence of cirrhosis was not evaluated.

Hepatitis C infected individuals who do not have cirrho-

sis have a much lower risk of developing HCC. 64 How-

ever, the transition from bridging ﬁbrosis to cirrhosis

cannot be determined clinically so that the clinician can-

not easily determine when these patients start to develop a

signiﬁcant increase in risk of HCC. For this reason the

EASL conference 3 suggested that surveillance may be of-

fered to patients with hepatitis C and cirrhosis or with

bridging ﬁbrosis or transition to cirrhosis. The cost-efﬁ-

cacy of this recommendation has not been evaluated.

Based on current knowledge, all patients with hepatitis C

and cirrhosis should undergo surveillance. Whether pa-

tients with bridging ﬁbrosis should also undergo surveil-

lance remains controversial.

Cirrhosis due to Causes Other Than Viral Hepatitis

The incidence of HCC in cirrhosis caused by diseases

other than viral hepatitis is, with some exceptions, not

accurately known. Most of the studies of the incidence of

HCC in alcoholic cirrhosis date from before the identiﬁ-

cation of the hepatitis C virus. Given that hepatitis C is

relatively frequent in alcoholics 75-77 most of the reported

HCC incidence rates in earlier studies must be over-esti-

mates. That alcoholic cirrhosis is a risk factor for HCC is

clear. In one study alcoholic liver disease accounted for

32% of all HCCs. 78 In an Austrian cohort with HCC

alcoholic liver disease was the risk factor in 35% of sub-

jects. 79 In the United States the approximate hospitaliza-

tion rate for HCC related to alcoholic cirrhosis is 8-9/

100,000/year compared to about 7/100,000/year for

hepatitis C. 80 This study did not determine the incidence

of HCC in alcoholic liver disease, but it does conﬁrm that

alcoholic cirrhosis is a signiﬁcant risk factor for HCC,

probably sufﬁcient to warrant surveillance for HCC.

With the recognition of steatohepatitis as a cause of

cirrhosis, has come the suspicion that this too is a risk

factor for HCC. No study to date has followed a sufﬁ-

ciently large group of such patients for long enough to

1212 BRUIX AND SHERMAN

HEPATOLOGY, November 2005

describe an incidence rate for HCC. In one cohort study

of patients with HCC 81 diabetes was found in 20% as the

only risk factor for HCC. Whether or not these patients

were cirrhotic was not noted. Non-alcoholic fatty liver

disease (NAFLD) has been described in cohorts of pa-

tients with HCC. 82,83 Since the incidence of HCC in

cirrhosis due to NAFLD is unknown it is not possible to

assess whether surveillance might be effective or cost-efﬁ-

cient. No recommendations can be made whether this

group should be screened for HCC or not. This does not

preclude the possibility that surveillance is beneﬁcial in

this group, and future data may change this recommen-

dation.

Patients with genetic hemochromatosis (GH) who

have established cirrhosis have an increased risk of

HCC. 84-86 The relative risk of HCC is about 20. The

standardized incidence ratio for HCC in cirrhotic GH is

92.9 (95% conﬁdence interval [CI] 25-237.9). The inci-

dence of HCC in cirrhosis due to GH is sufﬁciently high

(about 3%-4%/year) that these patients should be in-

cluded in surveillance programs. The incidence of HCC

in stage 4 primary biliary cirrhosis is about the same as in

cirrhosis due to hepatitis C. 87 For cirrhosis due to alpha

1-antitrypsin (AAT) deﬁciency, 88,89 or autoimmune hep-

atitis there are insufﬁcient data from cohort studies to

accurately assess HCC incidence.

Hepatitis C. There are a number of studies evaluat-

ing the effect of treatment of chronic hepatitis C on the

incidence of HCC. A single RCT in Japan suggested

that the incidence of HCC was reduced in both re-

sponders and non-responders to interferon. 95 These

results could not be conﬁrmed in a second RCT from

France. 96 The results of these other studies were sum-

marized in a meta-analysis, which concluded that the

beneﬁt is mainly seen in those who were successfully

treated, i.e. , had a sustained virological response, and

even then, the effect was small. 97 A number of studies

in Japan compared the incidence of HCC in treated

patients with that in historical controls. 15,64,98-103

These have suggested that there is a reduced incidence

of HCC in treated patients. However, no data demon-

strate that treating or eradicating hepatitis C com-

pletely eliminates the risk for HCC. Thus it seems that

patients with hepatitis C and cirrhosis who have

achieved viral clearance on therapy should, at least for

now, continue to undergo surveillance.

Note that patients with treated or spontaneously inac-

tivated chronic hepatitis B or C may show regression of

ﬁbrosis sufﬁcient to suggest reversal of cirrhosis. The risk

of HCC in these patients probably does not decrease pro-

portionately with the improvement in ﬁbrosis. There are

many theories about the pathogenesis of HCC in these

patients, but one common factor seems to be that re-

peated rounds of necrosis and regeneration are necessary.

The steps required to initiate the carcinogenic pathway

probably occur many years before the disease becomes

inactive, and so the threat of HCC remains even if ﬁbrosis

decreases. Regressed ﬁbrosis is not a reason to withhold

surveillance.

Treated Chronic Viral Hepatitis

Hepatitis B. There is as yet no convincing evidence

that interferon treatment of chronic hepatitis B reduces

the incidence of HCC. Studies in Europe suggested that

interferon therapy for chronic hepatitis B improved sur-

vival and reduced the incidence of HCC. 61,90,91 A study

from Taiwan also indicated that successful interferon

therapy, i.e. , the development of anti-HBe, was associated

with a reduced incidence of HCC. 92 However, in these

studies the event rate was low, and the sample sizes were

relatively small. In contrast, a non-randomized, but

matched controlled study fromHong Kong that included

a larger cohort followed for longer periods found that the

incidence of HCC was not decreased in the treated

group. 93 A single RCT suggests that lamivudine treat-

ment of chronic hepatitis B carriers with cirrhosis does

reduce the incidence of HCC, 94 but whether the risk re-

duction is sufﬁcient that surveillance becomes unneces-

sary is not clear. If a patient is a candidate for surveillance

before the institution of treatment, it seems prudent to

continue to offer surveillance even after therapy-induced

seroconversion or therapy-induced remission of inﬂam-

matory activity.

Other Predictive Factors for HCC

There are a number of factors associated with an

increased risk of HCC that are seen in patients at risk

for developing HCC. These include an elevated AFP

concentration, 104-106 presence of macroregenerative

nodules, 107 small and large cell dysplasia on biop-

sy, 62,108,109 irregular regeneration (irregular margins to

regenerative nodules) 110 and increased labeling index

for proliferating cell nuclear antigen or silver staining

of the nucloeolar organizing region. 111-115 Although

such patients are at more immediate risk of developing

HCC they will likely already be in surveillance pro-

grams because of other recognized risk factors such as

cirrhosis or chronic hepatitis B. The increased risk,

however, does not require a change in surveillance pro-

tocol.

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