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Journal of Hepatology 44 (2006) 810



Hepatocellular carcinoma in the United States. Lessons from a

population-based study in Medicare recipients
Maria Varela, Jordi Bruix*
BCLC Group, Liver Unit, Hospital Clnic, University of Barcelona, IDIBAPS, Villarroel 170, 08036 Barcelona, Catalonia, Spain

See Article, pages 158166

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 All these concepts are outdated.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
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 [35]. Hence, all hepatologists 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
* Corresponding author. Tel.: C34 93 227 9803; fax: C34 93 227 5792.
E-mail address: bruix@ub.edu (J. Bruix).

(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
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 [1012]. 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. ElSerag 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

0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

M. Varela, J. Bruix / Journal of Hepatology 44 (2006) 810

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 transarterial chemoembolization does not reach 2 and 1 year,
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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