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Management of Hepatocellular Carcinoma
UNIV.PROF.DR.CH. MUELLER
UNIVERSITAETSKLINIK FÜR INNERE MEDIZIN
IV
KLINISCHE ABTEILUNG FÜR
GASTROENTEROLOGIE UND HEPATOLOGIE
WAEHRINGER GÜRTEL 18-20
1090 WIEN
TEL: +43-1-40400-4792
FAX: +43-1-40400-4794
E-MAIL: CHRISTIAN.J.MUELLER@MEDUNIWIEN.AC.AT
Introduction: Hepatocellular carcinoma (HCC) is one of
the complications of chronic liver
disease and liver cirrhosis. It is the
leading cause of death from malignant
diseases worldwide. Hepatocellular
carcinoma is characterized by the almost
exclusive development in cirrhotic
livers:
less than 10% of HCC originate in
non-cirrhotic livers. The underlying
etiology of liver disease influences the
risk for HCC: patients with HBV, HCV or
genetic hemochromatosis associated
cirrhosis are at high risk, patients
with alcoholic cirrhosis and PBC are at
moderate risk and non cirrhotic HBV or
HCV carriers or patients with autoimmune
hepatitis associated cirrhosis have a
comparably low risk for HCC.
In the western world HCC is a disease of
elder patients (median age at diagnosis
around 60 years) whereas in developing
countries and in Southeast Asia it is
also very often seen in young people. In
industrialized nations HCC is
characteristically detected relatively
late in the course of the disease: in
more than 50% the tumour is already
multifocal at the time of diagnosis.
This advanced stage at diagnosis results
in a very low proportion of patients
eligible for liver resection or liver
transplantation.
Diagnosis: Every mass lesion in cirrhotic livers
should be considered suspicious of HCC
as long as not proven otherwise. Blood
supply for HCC nodules comes usually
from the hepatic artery whereas blood
supply to cirrhotic nodules is from the
portal vein. This difference is the
basis for contrast enhanced spiral CT to
detect HCC. However, not all tumour
nodules might be detectable by spiral
CT, some are only seen by ultrasound,
some others only using MRI techniques.
The most often used tumour marker
alpha-fetoprotein (AFP) has a moderate
sensitivity for detecting HCC. In about
20% of HCC AFP levels are normal and in
only one-third of tumours AFP levels are
>400ng/L and, therefore, considered
diagnostic. The definite diagnosis is
made by ultrasound-, CT- or MR-guided
biopsy. Tumour seeding along the path of
the needle has been observed in singular
cases, but is a rare complication
overall.
Prognosis: Due to the usually far advanced stage at
the time of diagnosis prognosis is poor.
Median survival time at the time of
diagnosis is around 8 months, but is
dependent on the stage of the liver
cirrhosis (Child A, median survival 21
months; Child C, median survival 2
months). Multivariate analysis of
various prognostic variables showed
several independent variables to be
associated with poor prognosis:
Bilirubin > 2mg/dl, Portal vein
thrombosis PTZ < 70%, AFP > 180mg/L.
Tumour mass > 50% of liver mass, and the
presence of enlarged lymph nodes.
Treatment of HCC: Several treatment modalities have been
proposed and vividly promoted; this
mirrors the generally insufficient
treatment success. Many prognostic
factors have been described of which the
overall liver function is of most
importance. Many patients with HCC don’t
die due to the tumour but due to
complications of the underlying liver
cirrhosis. A well preserved overall
liver function is also important
therapeutically because many treatment
methods don’t destroy the tumour only,
but also non-tumour bearing liver tissue
and might therefore contribute to liver
failure. Only randomized clinical trials
can establish the benefit of specific
treatment regimens. Unfortunately, most
of the randomized clinical studies for
treatment of HCC have produced only
negative or inconclusive results.
Despite the general lack of randomized
clinical trials with convincing results
several therapeutic strategies are
regularly used:
Liver transplantation: Liver transplantation, where available,
is the only treatment which treats the
tumour and the underlying precancerous
disease that is liver cirrhosis. At
present the so-called Mazzoferro-criteria
are most often used to determine
suitability of a patient for liver
transplantation: one tumour nodule less
than 5 cm in diameter or a maximum of 3
tumour nodules each less than 3 cm in
diameters. Liver transplantation in
those patients results in an overall
survival which is similar to that seen
in patients transplanted for liver
cirrhosis without tumours. In contrast,
liver transplantation in patients with
more advanced HCC is associated with a
high probability of recurrence of
disease and a clear decrease in survival
rate.
Tumour resection: Tumour resection is another potential a
curative approach, which, however, has
some problems of its own: mortality is
high, even in well compensated Child A
liver cirrhosis patients (up to 15%in
some series). Strict selection criteria
are necessary to reduce perioperative
mortality, which at the same time
reduces the number of eligible patients:
Less than 10% of patients with HCC in
industrialized countries are candidates
for resection therapy. In addition, the
risk of newly developing tumours might
be as high as 80-90% within 5 years.
Both, metastatic tumours of the primary
HCC as well as de novo HCC in the
remaining cirrhotic liver are seen.
(Chemo-) embolisation therapy: Embolisation therapy treats the tumour
by closing the tumour-feeding artery,
which usually comes from branches of the
hepatic artery. Various embolisation
materials are used: the oily contrast
medium lipiodol, gel foam preparations,
coils, or beads which might also be
loaded with cytostatic drugs (TACE =
transarterial (Chemo)Embolisation).
Embolisation leads to an ischemic
necrosis of the tumour. It might be, but
it is not completely clear, that the
addition of cytostatic drugs to the
embolisation material enhances the anti-tumour
effect. Most single randomized clinical
studies of embolisation therapy did not
show any convincing survival benefit.
However, a metaanalysis of 5 RTC’s
suggests a slight reduction in two year
mortality in patients treated with TACE.
Percutaneous alcohol installation
(PEI): An alternative approach is to destroy
the tumour by ultrasound-, CT- or MR-guided
alcohol instillation. HCC is a
hypervascular tumour surrounded by a
fibrotic capsule: injected 95% ethanol
diffuses within the HCC nodules, and
leads to selective tumour necroses.
In general, tumour nodules less than
3-5cm are well suited for such an
approach. The smaller the tumour the
higher the probability of a complete
tumour destruction. Some groups treat
HCC with larger diameters (up to 10cm),
others inject higher volumes of ethanol
(50-150ml) in one session in patients
under general anaesthesia. One advantage
of PEI is that it might also be applied
safely to patients with advanced liver
cirrhosis; clear contraindications are
Child C patients, massive ascites and
bleeding tendency. The therapeutic
effect might be documented with CT, MR
or ultrasound. Shrinkage of the tumour
is only observed to a small proportion
of treated patients, the disappearance
of contrast enhancement in contrast CT
is the more reliable parameter
indicating complete tumour necrosis. One
year survival with PEI is between
60-100% and is similar to
one-year-survival after HCC resection.
Radiofrequency ablation (RF): This method uses high frequency
alternate current which is applied via a
percutaneously inserted needle and
results in local heat necrosis of the
tumour. Its potential advantage compared
to PEI is its higher predictability of
the size of necrosis and its ability to
induce necrosis beyond the fibrotic
capsule of the tumour providing the
opportunity to produce 1cm safety rings
surrounding the tumour. Randomized
controlled trials show that RF ablation
has a better local anti-tumour effect
than PEI leading to improved local
control of the disease. Although some
RTC suggest a survival benefit of
patients treated with RF definite
superiority of RF ablation over PEI has
not been demonstrated. In addition,
about 25% of the lesions are not
treatable by RF ablation due to the
unfavourable location of the tumour.
Other local therapies: Other therapeutic procedures such as
microwave ablation, laser ablation, cryo-ablation
have been proposed and used in treatment
of HCC. However, these methods should
still be considered as experimental due
to limited experience.
Hormonal manipulation:
Anti-oestrogen: Several randomized controlled trials
with the oestrogen receptor blocker
tamoxifen have been performed and have
shown variable results. The biggest
double-blind placebo controlled study,
which included more than 200 patients
showed no survival benefit.
Somatostatin: The somatostatin analogue octreotide
showed a survival benefit in randomized
study of 58 patients with inoperable HCC
(Survival 12 months 37 vs. 13 % in
controls). However, two other randomized
trials showed no survival benefit
(median survival 1,9 vs. 1,9 months and
4.5 vs. 5 months respectively). It is
possible that the negative results of
the latter two studies are due to
selection of very late stage HCC
patients, a group in which it is
extremely difficult to show a survival
benefit.
Summary: More than 90% of HCC develop liver
cirrhosis patients. HCC is detected
usually very late. The median survival
after diagnosis is around 8 months.
Potentially curative treatment options
are liver transplantation (eligible
patient should have one tumour less than
5cm, or a maximum of 3 tumours less than
3 cm each) and resection of the tumour.
Surgery, however, is only an option in
the minority of patients with either HCC
non-cirrhotic livers or in cirrhotic
livers with well preserved hepatic
function (Child A cirrhosis). Patients
who are neither candidates for liver
transplantation or surgery might benefit
from local ablative therapy with TACE,
RF or PAI. A metaanalysis of randomized
controlled trials using TACE as compared
to supportive treatment showed a benefit
in survival of TACE treated patients. RF
promises better local tumour control
than PEI, it is, however, unclear
whether this can also translate into an
improved survival of patients. Patients
with advanced stage HCC might benefit
from treatment with somatostatin
analogues, which are well tolerated and
without major side effects. Prognosis of
patients with HCC usually depends more
dependent on stage of cirrhosis and on
complications of liver disease (variceal
bleeding, ascites and encephalopathy)
than on the growth of the tumour.
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