Editorial

Hepatocellular carcinoma in the United States. Lessons from apopulation-based study in Medicare recipients

Maria Varela, Jordi Bruix*

BCLC Group, Liver Unit, Hospital Clı́nic, University of Barcelona, IDIBAPS, Villarroel 170, 08036 Barcelona, Catalonia, Spain

0168-8278/$30.00 q 2005 European Association for the

doi:10.1016/j.jhep.2005.11.001

* Corresponding author. Tel.: C34 93 227 9803; fax: C

E-mail address: bruix@ub.edu (J. Bruix).

See Article, pages 158–166

The interest and research activity in diagnosis and

treatment of hepatocellular carcinoma (HCC) has increased

sharply over recent decades [1]. Twenty years ago, this

cancer was seen as a disease almost entirely restricted to

Asia and sub-Saharian Africa. It was equally assumed that

early diagnosis was unfeasible, that treatment was not

effective, that its prognosis was very poor with survival

rarely exceeding 3 months. All these concepts are outdated.

Several registries in Europe and America have shown that

the incidence of HCC has experienced a significant increase

over recent years and currently, HCC ranks among the five

most important cancer killers worldwide [2]. Still, the

majority of cases appear in Asia and sub-Saharian Africa,

but HCC incidence is not negligible in most areas of the

world.

As is commonly known, HCC appears in most cases

within a chronically diseased liver, the most frequent

etiologic agents being hepatitis B and C viruses and

excessive alcohol intake. Interestingly, modern cohort

studies have shown that HCC is now the leading cause of

death in patients with cirrhosis [3–5]. Hence, all hepatol-

ogists and healthcare providers involved in the management

of patients with liver disease are now aware of the increased

risk of cancer of their patients. Simultaneously, major effort

and importance is placed in developing guidelines and

protocols to deliver optimal healthcare to patients with

either suspected or proven HCC. Years ago, the European

Association for the Study of Liver Disease (EASL)

organised the Barcelona Monothematic Conference, where

a panel of experts produced the first Western document to

guide the diagnosis and treatment of patients with HCC [6].

The American Association for the Study of Liver Diseases

Study of the Liver. Pub

34 93 227 5792.

(AASLD) has recently published the Practice Guidelines for

the Management of HCC [7] and in the following months a

new document prepared by a panel of experts of EASL,

AASLD and the Japan Society of Hepatology that met at the

second Barcelona meeting on HCC will further homogenise

the management and research needs on a more worldwide

level.

These comments are relevant to frame the value and

message of the study by the group of El-Serag published in

this issue of the Journal [8]. This team has played a major

role in the definition of the importance of HCC in the United

States and the specific epidemiological profile in their

country. Their data have unequivocally depicted the

increase in the incidence of HCC (which has almost doubled

in the last 30 years) [9] and through the analysis of large

databases they have emphasised the role of viral infection,

alcoholism, diabetes and HIV [10–12]. The new study

further digs into the databases and tries to assess to what

extent the management of the HCC patients is adequate and/

or homogeneous and whether the outcome of the patients

fits into the expected figures. The results should represent a

concern for the authority responsible of health care delivery

to HCC patients within Medicare. There is significant

heterogeneity in the type of treatment offered and in some

instances the therapy applied does not adhere to the most

recent state of the art recommendations. In addition, the

survival registered in the database does not reproduce the

findings of modern cohort studies in which treatment

allocation is decided following a proper algorithm. El-

Serag et al. show that only 11% of the potential candidates

for transplantation were actually transplanted; that just 13%

patients for surgical resection received such therapy and,

finally, that only 14% of those apparently fit for local

ablation were treated. By contrast, 19% of patients with

HCC lesions O10 cm and 5% of patients with metastatic

Journal of Hepatology 44 (2006) 8–10

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M. Varela, J. Bruix / Journal of Hepatology 44 (2006) 8–10 9

disease underwent therapies with curative intent, while in

most referral Units they would have been dismissed because

of the well-known poor outcome [8]. As a whole, it appears

that some individuals who could have benefited from

therapy were not treated and some who were treated would

have been better served if they had been left untreated.

Obviously, all this rough interpretation should be

tempered because of the database limitations. The most

important of them is the fact that the database represents

a non-random segment of the population, whose

healthcare is provided by Medicare. Furthermore, the

database allows to extract a general view of the situation

regarding HCC management, but the data collected to

construct the database does not allow to perform an in

depth analysis to clarify why treatments were not offered

in some instances or why they were apparently indicated

in a controversial strategy. The retrospective analysis of

the database cannot ensure a proper diagnosis and

staging of the patients and obviously these critical points

in clinical decision making were largely heterogeneous

among centres. Furthermore, significant co-morbidity

cannot be accurately established and this may be the

most important reason to avoid therapy. The authors have

used an index to estimate presence of co-morbidities, but

even with this approach, the reason why treatment was

offered or denied is impossible to be ascertained.

Intriguingly enough, the authors show that there are

also major differences according to the location of the

patients. This means that the treatment strategy is not the

same all over the US, but the difference may also be the

result of some specific cultural or economic profile of the

population attended by Medicare in different states.

It could be argued that population based studies assessing

incidence, treatment allocation and survival are not

available. Hence, the study by El-Serag et al. may reflect

real life while cohort studies raised in referral Units merely

report the cases in best conditions that are evaluated in these

specific Centres. While this could be partially the case in the

provision of treatment and for overall survival, the argument

cannot be used to explain the outcome after therapies.

Current data applying adequate criteria indicate that

survival after resection, transplant or percutaneous ablation

should definitely exceed 50% at 3 years [7] and here we are

given figures that are far below these limits. Median survival

after transplantation is approximately less than 4 years, and

does not reach 3 years after surgical resection. Similarly,

median survival after percutaneous ablation and transarter-

ial chemoembolization does not reach 2 and 1 year,

respectively.

Do these comments suggest that the study by El-Serag

et al. has no value? Not at all! It is clear that HCC is an

emerging health problem that has not been adequately

dealt with in several countries. The present study

indicates that this is also true at least in some specific

populations within the US. This critical information

should be the trigger to set up the strategy to further

assess the gaps between state of the art knowledge and

its application in real life. Both EASL and AASLD have

made the effort to offer health care providers with

guidelines to deliver optimal care [6,7]. Furthermore, the

management and research in the US has been the focus

of specific conferences organised by AASLD and NIH,

that have prompted that liver cancer is now one of the

targets of a major research funding within the NIH action

plan of the liver disease section. This research activity

both in the experimental laboratory and in the clinical

setting should be instrumental to face the HCC

‘epidemic’ with proper cost-efficiency. In that sense, it

has to be stressed that the economic burden of HCC

management is not negligible. A recent analysis by Kim

et al. [13] has shown that the clinical activity related to

HCC management has markedly increased in the past 20

years and that this has a direct translation in costs.

According to these authors, the hospitalisation of HCC

patients in the US during the year 2000 may have had a

cost of $509 million, a figure that is compatible with the

estimate made by the American Gastroenterological

Association, that calculated all the costs associated with

HCC in 1998 to be $998 million [13].

In summary, while great improvements have been

achieved in the awareness of the relevance of HCC and

its increasing incidence, there is still a major need to

improve all the aspects related to its diagnosis and

management. Probably, Japan and Europe are ahead of

the US because the increase in HCC incidence

occurred earlier in these countries and thus, the need

to have the proper resources in place was a necessity

years before. Now, the problem has unequivocally

emerged in the US and the study by El-Serag et al.

shows that the healthcare delivery to HCC patients

within Medicare is not optimal. There is major room

for improvement and this will certainly take place in

the next few years.

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