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Liver Cancer
Reduced
incidence of HCC (liver cancer) post treatment
Q Successful treatment for HCV is supposed to reduce the
incidence of HCC & Lymphoma etc. Does this mean that the risk is
about the same as if you had never had HCV, or just less than it
would be without treatment? Also, does treatment predispose a person
to any other type of cancer, due to the toxic nature of the drugs
used to clear the virus?
A There is increasing
evidence that clearance of HCV stops liver disease progression and
thus decreases the risk of HCC but the data is quite hard to
interpret. If you have cirrhosis and are clear the risk is decreased
as we now think that 'fibrosis' may be more 'plastic' i.e.
reversible than previous thought. This is an interesting change in
viewpoint for hepatologists. So the decrease in risk depends on
whether an individual had cirrhosis. Someone with HCV who is
non-cirrhotic does not have an increased risk compared to the
general population. No, as far as I'm aware, treatment does not
predispose you to other cancers.
Celsion Corporation (NASDAQ: CLSN) and
Yakult Honsha Co., Ltd. (Tokyo: 2267)
announced today that the first patient has
been enrolled and treated in Japan as part
of Celsion's global Phase III ThermoDox HEAT
trial for the...
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article]
Celsion Corporation (NASDAQ:
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announced today that it has received official approval
from China's State Food and Drug Administration ("SFDA")
for its Clinical Trial Application for ThermoDox that
permits Celsion to include Chinese clinical trial sites
in its Phase III ThermoDox HEAT trial for the treatment
of primary liver cancer, also known as hepatocellular
carcinoma (HCC).
Today,
in an alarming move, the National Institute for Health
and Clinical Excellence (NICE) has, once again, proposed
to deny Nexavar® (sorafenib) for the treatment of
advanced hepatocellular carcinoma (HCC) - a form of
liver cancer...
[read
article]
NEW YORK (Reuters Health) - The risk of a
rare form of liver cancer called
intrahepatic cholangiocarcinoma, which
occurs in the bile ducts of the liver, is
significantly elevated in individuals who
are infected with hepatitis C virus (HCV),
according to a large "case-control" study of
US veterans.
HCV-infected individuals are also at
increased risk for another type of liver
cancer called hepatocellular carcinoma, the
study shows. Liver cancer is the third
leading cause of cancer deaths worldwide.
The findings stem from a look at 146,394
HCV-infected and 572,293 uninfected adults,
mostly men, who were followed for an average
of more than 2 years.
When comparing HCV-infected with HCV-uninfected
subjects, the risk of hepatocellular
carcinoma was 15-fold higher in the infected
group and the risk of intrahepatic
cholangiocarcinoma was 2.5-fold higher. The
risk of pancreatic cancer was 23 percent
higher.
Analyses adjusting for other variables,
such as alcohol use and inflammation of the
pancreas), confirmed the strong association
between HCV infection and hepatocellular
carcinoma and intrahepatic
cholangiocarcinoma. However, the association
between HCV and pancreatic cancer was no
longer statistically significant.
Dr. Hashem B. El-Serag, at the Houston VA
Medical Center, and colleagues there and at
the National Cancer Institute in Rockville,
Maryland, say the mixed findings of this
study regarding the association between HCV
and pancreatic cancer "merit additional
investigation."
"From a clinical perspective," they
conclude, "early intervention strategies,
including screening HCV-positive individuals
earlier or more rigorously, may improve the
outcomes for both hepatocellular carcinoma
and intrahepatic cholangiocarcinoma."
SOURCE: Hepatology, January 2009.
Experimental Treatment Liver
Cancer
Nov 2008
29 December 2008
Acculis Limited, the
leading UK microwave ablation system company, today announced the
extension of the worldwide launch of their pioneering Microwave
Tissue Ablation (MTA) system for the coagulation of soft tissue in
open surgery...
[read
article]
Development of
hepatocellular carcinoma in a patient 13 years after sustained
virological response to interferon against chronic hepatitis C:a
case report
http://7thspace.com
Although several recent reports
have shown that hepatocellular carcinoma (HCC) developed in patients
with chronic hepatitis C (CH-C) even after having a sustained
virological response (SVR) to interferon (IFN) therapy, it is not
common for HCC to develop more than 10 years after SVR. Case
presentation – A 73-year-old Japanese man with CH-C who achieved SVR
to IFN therapy 13 years ago was admitted into our hospital because
of huge multiple liver tumors along with marked elevation of the
tumor markers.
Several diagnostic modalities
strongly suggested HCC, and we performed histopathological
examination. After confirming the diagnosis as well-differentiated
HCC, we successfully treated these tumors with intensive combination
therapies.
Conclusions:
Our report highlights the need for careful follow-up for more than
10 years even if the patients with CH-C achieve SVR to IFN therapy.
Hepatocellular carcinoma is a cancer arising from the liver. It is also known as primary liver cancer
or hepatoma. The liver is made up of different cell types (e.g., bile ducts,
blood vessels, and fat-storing cells). However, liver cells (hepatocytes)
make up 80% of the liver tissue. Thus, the majority of primary liver cancers
(over 90 to 95%) arises from liver cells and is called hepatocellular cancer
or carcinoma.
When patients or physicians speak of liver cancer, however, they are
often referring to cancer that has spread to the liver, having originated in
other organs (such as the colon, stomach, pancreas, breast, and lung). More
specifically, this type of liver cancer is called metastatic liver disease
(cancer) or secondary liver cancer. Thus, the term liver cancer actually can
refer to either metastatic liver cancer or hepatocellular cancer. The
subject of this article is hepatocellular carcinoma, which I will refer to
as HCC.
HCC is the fifth most common cancer in the world. A deadly cancer, HCC will
kill almost all patients who have it within a year. In 1990, the World
Health Organization estimated that there were about 430,000 new cases of HCC
worldwide, and a similar number of patients died as a result of this
disease. About three quarters of the cases of HCC are found in Southeast
Asia (China, Hong Kong, Taiwan, Korea, and Japan). HCC is also very common
in sub-Saharan Africa (Mozambique and South Africa).
The frequency of HCC in Southeast Asia and sub-Saharan Africa is greater
than 20 cases per 100,000 population. In contrast, the frequency of HCC in
North America and Western Europe is much lower, less than 5 per 100,000
population. However, the frequency of HCC among native Alaskans is
comparable to that seen in Southeast Asia. Moreover, recent data show that
the frequency of HCC in the U.S. overall is rising. This increase is due
primarily to chronic hepatitis C , an infection of the liver that causes HCC.
In the U.S. the highest frequency of HCC occurs in immigrants from Asian
countries, where HCC is common. The frequency of HCC among Caucasians is the
lowest, whereas among African-Americans and Hispanics, it is intermediate.
The frequency of HCC is high among Asians because HCC is closely linked to
chronic hepatitis B infection. This is especially so in individuals who have
been infected with chronic hepatitis B for most of their lives. If you take
a world map depicting the frequency of chronic hepatitis B infection, you
can easily superimpose that map on a map showing the frequency of HCC.
The initial presentation (symptoms) of HCC in patients in areas of high
HCC frequency is quite different from that seen in low frequency areas.
Patients from high frequency areas usually start developing HCC in their
40’s, and the cancer is usually more aggressive. That is, the HCC presents
with severe symptoms and is inoperable (too advanced for surgery) at the
time of diagnosis. Also, in these areas, the frequency of HCC is three to
four times higher in men than in women, and most of these patients are
infected with chronic hepatitis B. In contrast, HCC in lower risk areas
occurs in patients in their 50’s and 60’s and the predominance of men is
less striking.
The role of hepatitis B virus (HBV) infection in causing HCC is well
established. Several lines of evidence point to this strong association. As
noted earlier, the frequency of HCC relates to (correlates with) the
frequency of chronic HBV infection. In addition, the patients with HBV who
are at greatest risk for HCC are men with HBV cirrhosis (scarring of the
liver) and a family history of HCC. Perhaps the most convincing evidence,
however, comes from a prospective (looking forward in time) study done in
the 1970’s in Taiwan involving male government employees over the age of 40.
In this study, the investigators found that the risk of developing HCC was
200 times higher among employees who had chronic HBV as compared to
employees without chronic HBV!
Studies in animals also have provided evidence that HBV can cause HCC.
For example, we have learned that HCC develops in other mammals that are
naturally infected with HBV-related viruses. Finally, by infecting
transgenic mice with certain parts of the hepatitis B virus, scientists
caused HCC to develop in mice that do not usually develop liver cancer.
(Transgenic mice are mice that have been injected with new or foreign
genetic material.)
How does chronic HBV cause HCC? In patients with both chronic HBV and
HCC, the genetic material of HBV is frequently found to be part of the
genetic material of the cancer cells. It is thought, therefore, that
specific regions of the HBV genome (genetic code) enter the genetic material
of the liver cells. This HBV genetic material may then disrupt the normal
genetic material in the liver cells, thereby causing the liver cells to
become cancerous.
The vast majority of HCC that is associated with chronic HBV occurs in
individuals who have been infected most of their lives. In areas where HBV
is not always present (endemic) in the community (e.g., the U.S.), HCC is
relatively uncommon. The reason for this is that most of the people with
chronic HBV in these areas acquired the infection as adults. However, HCC
can develop in individuals who acquired chronic HBV in adulthood if there
are other risk factors, such as chronic alcohol use or co-infection with
chronic HCV infection.
Hepatitis C infection
Hepatitis C virus (HCV) infection is also associated with the development of
HCC. In fact, in Japan, HCV is present in up to 75% of cases of HCC. As with
HBV, the majority of HCV patients with HCC have associated cirrhosis (liver
scarring). In several retrospective-prospective studies (looking backward
and forward in time) of the natural history of hepatitis C, the average time
to develop HCC after exposure to HCV was about 28 years. The HCC occurred
about 8 to 10 years after the development of cirrhosis in these patients
with hepatitis C. Several prospective European studies report that the
annual incidence (occurrence over time) of HCC in cirrhotic HCV patients
ranges from 1.4 to 2.5% per year.
In HCV patients, the risk factors for developing HCC include the presence
of cirrhosis, older age, male gender, elevated baseline alpha-fetoprotein
level (a blood tumor marker), alcohol use, and co-infection with HBV. Some
earlier studies suggested that HCV genotype 1b (a common genotype in the
U.S.) may be a risk factor, but more recent studies do not support this
finding.
The way in which HCV causes HCC is not well understood. Unlike HBV, the
genetic material of HCV is not inserted directly into the genetic material
of the liver cells. It is known, however, that cirrhosis from any cause is a
risk factor for the development of HCC. It has been argued, therefore, that
HCV, which causes cirrhosis of the liver, is an indirect cause of HCC.
On the other hand, there are some chronic HCV infected individuals who
have HCC without cirrhosis. So, it has been suggested that the core
(central) protein of HCV is the culprit in the development of HCC. The core
protein itself (a part of the hepatitis C virus) is thought to impede the
natural process of cell death or interfere with the function of a normal
tumor suppressor (inhibitor) gene (the p53 gene). The result of these
actions is that the liver cells go on living and reproducing without the
normal restraints, which is what happens in cancer.
Alcohol
Cirrhosis caused by chronic alcohol consumption is the most common
association of HCC in the developed world. Actually, we now understand that
many of these cases are also infected with chronic HCV. The usual setting is
an individual with alcoholic cirrhosis who has stopped drinking for ten
years, and then develops HCC. It is somewhat unusual for an actively
drinking alcoholic to develop HCC. What happens is that when the drinking is
stopped, the liver cells try to heal by regenerating (reproducing). It is
during this active regeneration that a cancer-producing genetic change
(mutation) can occur, which explains the occurrence of HCC after the
drinking has been stopped.
Patients who are actively drinking are more likely to die from non-cancer
related complications of alcoholic liver disease (e.g., liver failure).
Indeed, patients with alcoholic cirrhosis who die of HCC are about 10 years
older than patients who die of non-cancer causes. Finally, as noted above,
alcohol adds to the risk of developing HCC in patients with chronic HCV or
HBV infections.
Aflatoxin B1
Aflatoxin B1 is the most potent liver cancer-forming chemical known. It is a
product of a mold called Aspergillus flavus, which is found in food that has
been stored in a hot and humid environment. This mold is found in such foods
as peanuts, rice, soybeans, corn, and wheat. Aflatoxin B1 has been
implicated in the development of HCC in Southern China and Sub-Saharan
Africa. It is thought to cause cancer by producing changes (mutations) in
the p53 gene. These mutations work by interfering with the gene’s important
tumor suppressing (inhibiting) functions.
Drugs, medications, and chemicals
There are no medications that cause HCC, but female hormones (estrongens)
and protein-building (anabolic) steroids are associated with the development
of hepatic adenomas. These are benign liver tumors that may have the
potential to become malignant (cancerous). Thus, in some individuals,
hepatic adenoma can evolve into cancer.
Certain chemicals are associated with other types of cancers found in the
liver. For example, thorotrast, a previously used contrast agent for
imaging, caused a cancer of the blood vessels in the liver called hepatic
angiosarcoma. Also, vinyl chloride, a compound used in the plastics
industry, can cause hepatic angiosarcomas that appear many years after the
exposure.
Hemochromatosis
HCC will develop in up to 30% of patients with hereditary hemochromatosis. Patients at the greatest risk are those who develop
cirrhosis with their hemochromatosis. Unfortunately, once cirrhosis is
established, effective removal of excess iron (the treatment for
hemochromatosis) will not reduce the risk of developing HCC.
Cirrhosis
Individuals with most types of cirrhosis of the liver are at an increased
risk of developing HCC. In addition to the conditions described above
(hepatitis B, hepatitis C, alcohol, and hemochromatosis), alpha 1
anti-trypsin deficiency, a hereditary condition that can cause emphysema and
cirrhosis, may lead to HCC. Liver cancer is also strongly associated with
hereditary tyrosinemia, a childhood biochemical abnormality that results in
early cirrhosis.
Certain causes of cirrhosis are less frequently associated with HCC than
are other causes. For example, HCC is rarely seen with the cirrhosis in
Wilson’s disease (abnormal copper metabolism) or primary
sclerosing cholangitis (chronic scarring and narrowing of the
bile ducts). It used to be thought that HCC is rarely found in primary
biliary cirrhosis (PBC) as well. Recent studies, however, show
that the frequency of HCC in PBC is comparable to that in other forms of
cirrhosis.
The initial symptoms (the clinical presentations) of HCC are variable. In
countries where HCC is very common, the cancer generally is discovered at a
very advanced stage of disease for several reasons. For one thing, areas
where there is a high frequency of HCC are generally developing countries
where access to healthcare is limited. For another, screening examinations
for patients at risk for developing HCC are not available in these areas. In
addition, patients from these regions actually have more aggressive HCC
disease. In other words, the tumor usually reaches an advanced stage and
causes symptoms more rapidly. In contrast, patients in areas of low HCC
frequency tend to have HCC tumors that progress more slowly and, therefore,
remain without symptoms longer.
Abdominal pain is the most common symptom of HCC and usually signifies a
very large tumor or widespread involvement of the liver. Additionally,
unexplained weight loss or unexplained fevers are warning signs of HCC in
patients with cirrhosis. These symptoms are less common in individuals with
HCC in the U.S. because these patients are usually diagnosed at an earlier
stage. However, whenever the overall health of a patient with cirrhosis
deteriorates, every effort should be made to look for HCC.
A very common initial presentation of HCC in a patient with compensated
cirrhosis (no complications of liver disease) is the sudden onset of a
complication. For example, the sudden appearance of ascites (abdominal fluid
and swelling), jaundice (yellow color of the skin), or muscle wasting without causative
(precipitating) factors (e.g., alcohol consumption) suggests the possibility
of HCC. What’s more, the cancer can invade and block the portal vein (a
large vein that brings blood to the liver from the intestine and spleen).
When this happens, the blood will travel paths of less resistance, such as
through esophageal veins. This causes increased pressure in these veins,
which results in dilated (widened) veins called esophageal varices. The
patient then is at risk for hemorrhage from the rupture of the varices into
the gastrointestinal tract. Rarely, the cancer itself can rupture and bleed
into the abdominal cavity, resulting in bloody ascites.
On physical examination, an enlarged, sometimes tender, liver is the most
common finding. HCCs are very vascular (containing many blood vessels)
tumors. Thus, increased amounts of blood feed into the hepatic artery
(artery to the liver) and cause turbulent blood flow in the artery. The
turbulence results in a distinct sound in the liver (hepatic bruit) that can
be heard with a stethoscope in about one quarter to one half of patients
with HCC. Any sign of advanced liver disease (e.g., ascites, jaundice, or
muscle wasting) means a poor prognosis. Rarely, a patient with HCC can
become suddenly jaundiced when the tumor erodes into the bile duct. The
jaundice occurs in this situation because both sloughing of the tumor into
the duct and bleeding that clots in the duct can block the duct.
In advanced HCC, the tumor can spread locally to neighboring tissues or,
through the blood vessels, to elsewhere in the body (distant metastasis).
Locally, HCC can invade the veins that drain the liver (hepatic veins). The
tumor can then block these veins, which results in congestion of the liver.
The congestion occurs because the blocked veins cannot drain the blood out
of the liver. (Normally, the blood in the hepatic veins leaving the liver
flows through the inferior vena cava, which is the largest vein that drains
into the heart.) In African patients, the tumor frequently blocks the
inferior vena cava. Blockage of either the hepatic veins or the inferior
vena cava results in a very swollen liver and massive formation of ascites.
In some patients, as previously mentioned, the tumor can invade the portal
vein and lead to the rupture of esophageal varices.
Regarding the distant metastases, HCC frequently spreads to the lungs,
presumably by way of the blood stream. Usually, patients do not have
symptoms from the lung metastases, which are diagnosed by radiologic (x-ray)
studies. Rarely, in very advanced cases, HCC can spread to the bone or
brain.
Liver cancer is not diagnosed by routine blood tests, including a standard
panel of liver tests. This is why the diagnosis of HCC depends so much on
the vigilance of the physician screening with a tumor marker
(alpha-fetoprotein) in the blood and radiological imaging studies. Since
most patients with HCC have associated liver disease (cirrhosis), their
liver blood tests may not be normal to begin with. If these blood tests
become abnormal or worsen due to HCC, this usually signifies extensive
cancerous involvement of the liver. At that time, any medical or surgical
treatment would be too late.
Sometimes, however, other abnormal blood tests can indicate the presence
of HCC. Remember that each cell type in the body contains the full
complement of genetic information. What differentiates one cell type from
another is the particular set of genes that are turned on or off in that
cell. When cells become cancerous, certain of the cell’s genes that were
turned off may become turned on. Thus, in HCC, the cancerous liver cells may
take on the characteristics of other types of cells. For example, HCC cells
sometimes can produce hormones that are ordinarily produced in other body
systems. These hormones then can cause certain abnormal blood tests, such as
a high red blood count (erythrocytosis), low blood sugar (hypoglycemial)
and high blood calcium (hypercalcemia).
Another abnormal blood test, high serum cholesterol
(hypercholesterolemia), is seen in up to 10% of patients from Africa with
HCC. The high cholesterol occurs because the liver cancer cells are not able
to turn off (inhibit) their production of cholesterol. (Normal cells are
able to turn off their production of cholesterol.)
There is no reliable or accurate screening blood test for HCC. The most
widely used biochemical blood test is alpha-fetoprotein (AFP), which is a
protein normally made by the immature liver cells in the fetus. At birth,
infants have relatively high levels of AFP, which fall to normal adult
levels by the first year of life. Also, pregnant women carrying babies with
neural tube defects may have high levels of AFP. (A neural tube defect is an
abnormal fetal brain or spinal cord that is caused by folic acid deficiency
during pregnancy.)
In adults, high blood levels (over 500 nanograms/milliliter) of AFP are
seen in only three situations:
HCC
Germ cell tumors (cancer of the testes and ovaries)
Metastatic cancer in the liver (originating in other organs)
Several assays (tests) for measuring AFP are available. Generally, normal
levels of AFP are below 10 ng/ml. Moderate levels of AFP (even almost up to
500 ng/ml) can be seen in patients with chronic hepatitis. Moreover, many
patients with various types of acute and chronic liver diseases without
documentable HCC can have mild or even moderate elevations of AFP.
The sensitivity of AFP for HCC is about 60%. In other words, an elevated
AFP blood test is seen in about 60% of HCC patients. That leaves 40% of
patients with HCC who have normal AFP levels. Therefore, a normal AFP does
not exclude HCC. Also, as noted above, an abnormal AFP does not mean that a
patient has HCC. It is important to note, however, that patients with
cirrhosis and an abnormal AFP, despite having no documentable HCC, still are
at very high risk of developing HCC. Thus, any patient with cirrhosis and an
elevated AFP, particularly with steadily rising blood levels, will either
most likely develop HCC or actually already have an undiscovered HCC.
An AFP greater than 500 ng/ml is very suggestive of HCC. In fact, the
blood level of AFP loosely relates to (correlates with) the size of the HCC.
Finally, in patients with HCC and abnormal AFP levels, the AFP may be used
as a marker of response to treatment. For example, an elevated AFP is
expected to fall to normal in a patient whose HCC is successfully removed
surgically (resected).
There are a number of other HCC tumor markers that currently are research
tools and not generally available. These include
des-gamma-carboxyprothrombin (DCP), a variant of the
gamma-glutamyltransferase enzymes, and variants of other enzymes (e.g.,
alpha-L-fucosidase), which are produced by normal liver cells. (Enzymes are
proteins that speed up biochemical reactions.) Potentially, these blood
tests, used in conjunction with AFP, could be very helpful in diagnosing
more cases of HCC than with AFP alone.
Imaging studies play a very important role in the diagnosis of HCC. A good
study can provide information as to the size of the tumor, the number of
tumors, and whether the tumor has involved major blood vessels locally or
spread outside of the liver. There are several types of studies, each having
its merits and disadvantages. In practice, several studies combined often
complement each other. On the other hand, a plain X-ray is not very helpful,
and therefore, is not routinely done in the diagnostic work-up of HCC.
Further, there is no practical role for nuclear medicine scans of the liver
and spleen in the work-up for HCC. Such scans are not very sensitive and
they provide no additional information beyond that provided by the other (ultrasound,
CT, and MRI) scans.
Ultrasound examination is usually the first study ordered if HCC is
suspected in a patient. The accuracy of an ultrasound depends very much on
the technician and radiologist who perform the study (operator dependent).
Studies from Japan and Taiwan report that ultrasound is the most sensitive
imaging study for diagnosing and characterizing HCC. But you should know
that in these studies, highly experienced individuals performed the scans
and spent up to one hour scanning each patient suspected of having HCC. An
ultrasound has the advantages of not requiring intravenous contrast material
and not involving radiation. Moreover, the price of an ultrasound is quite
low as compared to the other types of scans.
Computerized axial tomography (CT scan) is a very common study used in
the U.S. for the work-up of tumors in the liver. The ideal CT study is a
multi-phase, spiral CT scan using oral and intravenous contrast material.
Pictures are taken in three phases:
Without intravenous contrast
With intravenous contrast (enhanced imaging) that highlights the
arterial system (arterial phase)
When the contrast is in the venous phase
The pictures are taken at very frequent intervals (thin slices) as the
body is moved through the CT scanner. Many radiologists use a specific
protocol that determines how the contrast is infused in relation to how the
pictures are taken. Therefore, CT is much less operator-dependent than is
ultrasound. However, CT is considerably more expensive. Furthermore, CT
requires the use of contrast material, which has the potential risks of an
allergic reaction and adverse effects on kidney function.
There are several variations to CT scanning. For example, in a CT
angiogram, which is a highly invasive (enters a part of the body) study,
intravenous contrast is selectively infused through the hepatic artery
(artery to the liver). The purpose is to highlight the vessels for better
visualization of them by the CT scan. Also, in Japan, an oily contrast
material called lipiodol, which is selectively taken up by HCC cells, has
been used with CT. The purpose of this approach is to improve the
sensitivity of the scan. That is to say, the goal is to increase the
percentage of abnormal CT scans in patients who have HCC.
Magnetic resonance imaging (MRI) can provide very clear images of the
body. Its advantage over CT is that MRI can provide sectional views of the
body in different planes. The technology has evolved to the point that the
newer MRIs can actually reconstruct images of the biliary tree (bile ducts
and gallbladder) and of the arteries and veins of the liver. (The biliary
tree transports bile from the liver to the duodenum, the first part of the
intestine.) MRI studies can be made even more sensitive by using intravenous
contrast material (e.g., gadolinium).
MRI scans are very expensive and there is tremendous variability in the
quality of the images. The quality depends on the age of the machine and the
ability of the patients to hold their breath for up to 15 to 20 seconds at a
time. Furthermore, many patients, because of claustrophobia, cannot tolerate
being in the MRI scanner. However, the current open MRI scanners generally
do not provide as high quality images as the closed scanners do.
Advances in ultrasound, CT, and MRI technology have almost eliminated the
need for angiography. An angiography procedure involves inserting a catheter
into the femoral artery (in the groin) through the aorta, and into the
hepatic artery, the artery that supplies blood to the liver. Contrast
material is then injected, and X-ray pictures of the arterial blood supply
to the liver are taken. An angiogram of HCC shows a characteristic blush
that is produced by newly formed abnormal small arteries that feed the tumor
(neovascularization).
What, then, is the best imaging study for diagnosing HCC? There is no
simple answer. Many factors need to be taken into consideration. For
example, is the diagnosis of HCC known or is the scan being done for
screening? What is the expertise of doctors in the patient’s area? What is
the quality of the different scanners at a particular facility? Are there
economic considerations? Does the patient have any other conditions that
need to be considered, such as claustrophobia or kidney impairment? Does the
patient have any hardware, e.g., a pacemaker or metal prosthetic device? (The hardware would make doing an
MRI impossible.)
If you live in Japan or Taiwan and have access to a radiologist or
hepatologist with expertise in ultrasound, then it may be as good as a CT
scan. Ultrasound is also the most practical (easier and cheaper) for regular
screening (surveillance). In North America, a multi-phase spiral CT scan is
probably the most accurate type of scan. However, for patients with impaired
renal function or who have access to a state-of-the-art MRI scanner, the MRI
may be the diagnostic scan of choice. Finally, keep in mind that the
technology of ultrasound, CT, and MRI is ever evolving with the development
of better machines and the use of special contrast materials to further
characterize the tumors.
In theory, a definitive diagnosis of HCC is always based on microscopic
(histological) confirmation. However, some liver cancers are well
differentiated, which means they are made up of nearly fully developed,
mature liver cells (hepatocytes). Therefore, these cancers can look very
similar to non-cancerous liver tissue under a microscope. Moreover, not all
pathologists are trained to recognize the subtle differences between
well-differentiated HCC and normal liver tissue. Also, some pathologists can
mistake HCC for adenocarcinoma in the liver. An adenocarcinoma is a
different type of cancer, and, as previously mentioned, it originates from
outside of the liver. Most importantly, a metastatic adenocarcinoma would be
treated differently from a primary liver cancer (HCC). Therefore, all of
this considered, it is important that an expert liver pathologist review the
tissue slides of liver tumors in questionable situations.
Tissue can be sampled with a very thin needle. This technique is called
fine needle aspiration. When a larger needle is used to obtain a core of
tissue, the technique is called a biopsy. Generally, radiologists, using
ultrasound or CT scans to guide the placement of the needle, perform the
biopsies or fine needle aspirations. The most common risk of the aspiration
or biopsy is bleeding, especially because HCC is a tumor that is very
vascular (contains many blood vessels). Rarely, new foci (small areas) of
tumor can be seeded (planted) from the tumor by the needle into the liver
along the needle track.
The aspiration procedure is safer than a biopsy with less risk for
bleeding. However, interpretation of the specimen obtained by aspiration is
more difficult because often only a cluster of cells is available for
evaluation. Thus, a fine needle aspiration requires a highly skilled
pathologist. Moreover, a core of tissue obtained with a biopsy needle is
more ideal for a definitive diagnosis because the architecture of the tissue
is preserved. The point is that sometimes a precise diagnosis can be
important clinically. For example, some studies have shown that the degree
of differentiation of the tumor may predict the patient’s outcome
(prognosis). That is to say, the more differentiated (resembling normal
liver cells) the tumor is, the better the prognosis.
The natural history of HCC depends on the stage of the tumor and the
severity of associated liver disease (e.g., cirrhosis) at the time of
diagnosis. For example, a patient with a 1 cm tumor with no cirrhosis has a
greater than 50% chance of surviving 3 years, even without treatment. In
contrast, a patient with multiple tumors involving both lobes of the liver
(multicentric tumors) with decompensated cirrhosis (signs of liver failure)
is unlikely to survive more than 6 months, even with treatment.
What are the predictors of a poor outcome? Our knowledge of the prognosis
is based on studying many patients with HCC, separating out their clinical
characteristics, and relating them to the outcome. Grouped in various
categories, the unfavorable clinical findings include;
Population characteristics (demographics); male gender, older age, or
alcohol consumption.
Symptoms; weight loss or decreased appetite.
Signs of impaired liver function; jaundice, ascites, or encephalopathy
(altered mental state).
Staging of tumor (based on imaging or surgical findings); more than
one tumor, tumor over 3cm (almost 1¼ inches), tumor invasion of local
blood vessels (portal and/or hepatic vein), tumor spread outside of the
liver (to lymph nodes or other organs).
There are various systems for staging HCC. Some systems look at clinical
findings while others rely solely on pathological (tumor) characteristics.
It makes the most sense to use a system that incorporates a combination of
clinical and pathological elements. In any event, it is important to stage
the cancer because staging can provide guidelines not only for predicting
outcome (prognosis) but also for decisions regarding treatment.
The doubling time for a cancer is the time it takes for the tumor to
double in size. For liver cancer, the doubling time is quite variable,
ranging from one month to eighteen months. This kind of variability tells us
that every patient with HCC is unique. Therefore, an assessment of the
natural history and the evaluation of different treatments are very
difficult. Nevertheless, in patients with a solitary HCC that is less than 3
cm, with no treatment, we can expect that 90% of the patients will survive
(live) for one year, 50% for three years, and 20% for five years. In
patients with more advanced disease, we can expect that 30% will survive for
one year, 8% for three years, and none for five years.
The treatment options are dictated by the stage of HCC and the overall
condition of the patient. The only proven cure for HCC is liver
transplantation for a solitary,small(<3cm) tumor. Now, many physicians may
dispute this statement. They may argue that a small tumor can be surgically
removed (partial hepatic resection) without the need for a liver
transplantation. Moreover, they may claim that the one and three year
survival rates for resection are perhaps comparable to those for liver
transplantation.
However, most patients with HCC also have cirrhosis of the liver and
would not tolerate liver resection surgery. But, they probably could
tolerate the transplantation operation, which involves removal of the
patient’s entire diseased liver just prior to transplanting a donor liver.
Furthermore, many patients who undergo hepatic resections will develop a
recurrence of HCC elsewhere in the liver within several years. In fact, some
experts believe that once a liver develops HCC, there is a tendency for that
liver to develop other tumors at the same time (synchronous multicentric
occurrence) or at a later time (metachronous multicentric occurrence).
The results of the various medical treatments (chemotherapy,
chemoembolization, ablation, and proton beam therapy) remain disappointing.
Moreover, for reasons noted earlier (primarily the variability in natural
history), there have been no systematic study comparisons of the different
treatments. As a result, individual patients will find that the various
treatment options available to them depend largely on the local expertise.
How do we know if a particular treatment worked for a particular patient?
Well, hopefully, the patient will feel better. However, a clinical response
to treatment is usually defined more objectively. Thus, a response is
defined as a decrease in the size of the tumor on imaging studies along with
a reduction of the alpha-fetoprotein in the blood, if the level was elevated
prior to treatment.
The most commonly used systemic chemotherapeutic agents are doxorubicin
(Adriamycin) and 5-fluorouracil (5 FU). These drugs are used together or in
combination with new experimental agents. These drugs are quite toxic and
results have been disappointing. A few studies suggest some benefit with
tamoxifen (Nolvadex) but just as many studies show no advantage. Octreotide
(Sandostatin) given as an injection was shown in one study to slow down the
progression of large HCC tumors, but so far, no other studies have confirmed
this benefit.
Hepatic arterial infusion of chemotherapy
The normal liver gets its blood supply from two sources; the portal vein
(about 70%) and the hepatic artery (30%). However, HCC gets its blood
exclusively from the hepatic artery. Making use of this fact, investigators
have delivered chemotherapy agents selectively through the hepatic artery
directly to the tumor. The theoretical advantage is that higher
concentrations of the agents can be delivered to the tumors without
subjecting the patients to the systemic toxicity of the agents.
In reality, however, much of the chemotherapeutic agents does end up in
the rest of the body. Therefore, selective intra-arterial chemotherapy can
cause the usual systemic (body-wide) side effects. In addition, this
treatment can result in some regional side effects, such as inflammation of
the gallbladder (cholecystitis), intestinal and stomach ulcers, and
inflammation of the pancreas (pancreatitis ). HCC patients with advanced
cirrhosis may develop liver failure after this treatment. Well then, what is
the benefit of intra-arterial chemotherapy? The bottom line is that fewer
than 50% of patients will experience a reduction in tumor size.
An interventional radiologist (one who does therapeutic procedures)
usually carries out this procedure. The radiologist must work closely with
an oncologist (cancer specialist), who determines the amount of chemotherapy
that the patient receives at each session. Some patients may undergo repeat
sessions at 6 to 12 week intervals. This procedure is done with the help of
fluoroscopy (type of x-ray) imaging. A catheter (long, narrow tube) is
inserted into the femoral artery in the groin and is threaded into the aorta
(the main artery of the body). From the aorta, the catheter is advanced into
the hepatic artery. Once the branches of the hepatic artery that feed the
liver cancer are identified, the chemotherapy is infused. The whole
procedure takes one to two hours, and then the catheter is removed.
The patient generally stays in the hospital overnight for observation. A
sandbag is placed over the groin to compress the area where the catheter was
inserted into the femoral artery. The nurses periodically check for signs of
bleeding from the femoral artery puncture. They also check for the pulse in
the foot on the side of the catheter insertion to be sure that the femoral
artery is not blocked as a result of the procedure. (Blockage would be
signaled by the absence of a pulse.)
Generally, the liver tests increase (get worse) during the two to three
days after the procedure. This worsening of the liver tests is actually due
to death of the tumor (and some non-tumor) cells. The patient may experience
some post-procedure abdominal pain and low-grade fever. However, severe
abdominal pain and vomiting suggest that a more serious complication has
developed. Imaging studies of the liver are repeated in 6 to 12 weeks to
assess the size of the tumor in response to the treatment.
This technique takes advantage of the fact that HCC is a very vascular
(contains many blood vessels) tumor and gets its blood supply exclusively
from the branches of the hepatic artery. This procedure is similar to
intra-arterial infusion of chemotherapy. But in TACE, there is the
additional step of blocking (embolizing) the small blood vessels with
different types of compounds, such as gelfoam or even small metal coils.
Thus, TACE has the advantages of exposing the tumor to high concentrations
of chemotherapy and confining the agents locally since they are not carried
away by the blood stream. At the same time, this technique deprives the
tumor of its needed blood supply, which can result in the damage or death of
the tumor cells.
The type and frequency of complications of TACE and intra-arterial
chemotherapy are similar. The potential disadvantage of TACE is that
blocking the feeding vessels to the tumor(s) may make future attempts at
intra-arterial infusions impossible. Moreover, so far, there are no
head-to-head studies directly comparing the effectiveness of intra-arterial
infusion versus chemoembolization. In Japan, the chemotherapeutic agents are
mixed with lipiodol. The idea is that since the tumor cells preferentially
take up lipiodol, they would likewise take up the chemotherapy. This
Japanese technique has not yet been validated in head-to-head comparisons
with conventional TACE.
What are the benefits of TACE? In one large study involving several
institutions in Italy, chemoembolization did not seem to be beneficial.
Patients who did not undergo TACE lived as long as patients who received
TACE, even though the tumors were more likely to shrink in size in patients
who were treated. Does this mean that TACE or intra-arterial chemotherapy
does not work? Maybe, maybe not.
Studies in Japan have shown that TACE can downstage HCC. In other words,
the tumors shrank enough to lower (improve) the stage of the cancer. From
the practical point of view, shrinking the tumor creates the option for
surgery in some of these patients. Otherwise, these patients had tumors that
were not operable (eligible for operation) because of the initial large size
of their tumors. More importantly, these same studies showed an improvement
in survival in patients whose tumors became considerably smaller. In the
U.S., trials are underway to see whether doing TACE before liver
transplantation increases patient survival as compared to liver
transplantation without TACE.
It is safe to say that TACE or intra-arterial chemoinfusion are
palliative treatment options for HCC. This means that these procedures can
provide relief or make the disease less severe. However, they are not
curative (do not result in a cure). Fewer than 50% of patients will have
some shrinkage in tumor size. Further, they can be used only in patients
with relatively preserved liver function. The reason for this is that these
procedures, as mentioned previously, can lead to liver failure in
individuals with poor liver function.
In the U.S., RFA therapy has become the ablation (tissue destruction)
therapy of choice among surgeons. The surgeon can perform this procedure
laparoscopically (through small holes in the abdomen) or during open
exploration of the abdomen. In some instances, the procedure can be done
without opening the abdomen by just using ultrasound for visual guidance.
In RFA, heat is generated locally by a high frequency, alternating
current that flows from the electrodes. A probe is inserted into the center
of the tumor and the non-insulated electrodes, which are shaped like prongs,
are projected into the tumor. The local heat that is generated melts the
tissue (coagulative necrosis) that is adjacent to the probe. The probe is
left in place for about 10 to 15 minutes. The whole procedure is monitored
visually by ultrasound scanning. The ideal size of an HCC tumor for RFA is
less than 3 cm. Larger tumors may require more than one session. This
treatment should be viewed as palliative (providing some relief), not
curative.
Percutaneous ethanol (alcohol) injection
In this technique, pure alcohol is injected into the tumor through a very
thin needle with the help of ultrasound or CT visual guidance. Alcohol
induces tumor destruction by drawing water out of tumor cells (dehydrating
them) and thereby altering (denaturing) the structure of cellular proteins.
It may take up to five or six sessions of injections to completely destroy
the cancer. The ideal patient for alcohol injection has fewer than three HCC
tumors, each of which is:
well defined (distinct margins)
less than 3cm in diameter
surrounded by a shell consisting of scar tissue (fibrous
encapsulation)
not near the surface of the liver
Additionally, patients with HCC undergoing alcohol injection should have
no signs of chronic liver failure, such as ascites or jaundice. (Patients
with liver failure would not be able to tolerate the alcohol injections.)
The most common side effect of alcohol injection is leakage of alcohol
onto the surface of the liver and into the abdominal cavity, thereby causing
pain and fever. It is important that the location of the tumor relative to
the adjacent blood vessels and bile ducts is clearly identified. The reason
for needing to locate these structures is to avoid injuring them during the
procedure and causing bleeding, bile duct inflammation, or bile leakage.
This technique is able to deliver high doses of radiation to a defined local
area. Proton beam therapy is used in the treatment of other solid tumors as
well. There are not much data yet regarding the efficacy of this treatment
in HCC. The ideal patient is one with only asmall(<5 cm) solitary lesion. To
have this procedure done, the patient actually is fitted with a body cast so
that he or she can be placed in the identical position for each session.
Therapy is conducted daily for 15 days. Preliminary data from the U.S.
suggest similar effectiveness as seen with TACE or ablation therapy. It is
not known, however, whether this type of radiation treatment prolongs the
life of the patient.
How do these various medical treatment procedures compare to each
other? We really don’t know because there are no head-to-head studies
comparing chemotherapy, chemoembolization, ablation techniques, and proton
beam therapy to each other. Most reports deal with a heterogeneous group of
patients who have undergone only one specific treatment procedure or
another. Therefore, selection of a treatment option for a particular patient
will depend primarily on the expertise of the doctors in the patient’s area.
Studies are also needed to evaluate combinations of these procedures (e.g.,
proton beam and TACE). Now, what about surgery?
Surgical options are limited to individuals whose tumors are less than 5 cm
and confined to the liver, with no invasion of the blood vessels.
Liver resection
The goal of liver resection is to completely remove the tumor and the
appropriate surrounding liver tissue without leaving any tumor behind. This
option is limited to patients with one or two small (3cm or less) tumors and
excellent liver function, ideally without associated cirrhosis. As a result
of these strict guidelines, in practice, very few patients with HCC can
undergo liver resection. The biggest concern about resection is that
following the operation, the patient can develop liver failure. The liver
failure can occur if the remaining portion of the liver is inadequate to
provide the necessary support for life. Even in carefully selected patients,
about 10% of them are expected to die shortly after surgery, usually as a
result of liver failure.
When a portion of a normal liver is removed, the remaining liver can grow
back (regenerate) to the original size within one to two weeks. A cirrhotic
liver, however, cannot grow back. Therefore, before resection is performed
for HCC, the non-tumor portion of the liver should be biopsied to determine
whether there is associated cirrhosis.
For patients whose tumors are successfully resected, the five-year
survival is about 30 to 40%. This means that 30 to 40 % of patients who
actually undergo liver resection for HCC are expected to live five years.
Many of these patients, however, will have a recurrence of HCC elsewhere in
the liver. Moreover, it should be noted that the survival rate of untreated
patients with similar sized tumors and similar liver function is probably
comparable. Some studies from Europe and Japan have shown that survival
rates with alcohol injection or radiofrequency ablation procedures are
comparable to the survival rates of those patients who underwent resection.
But again, the reader should be cautioned that there are no head-to-head
comparisons of these procedures versus resection.
Liver transplantation
Liver transplantation has become an accepted treatment for patients with
end-stage (advanced) liver disease of various types (e.g., chronic hepatitis
B and C, alcoholic cirrhosis, primary biliary cirrhosis, and sclerosing
cholangitis). Survival rates for these patients without HCC are 90% at one
year, 80% at three years, and 75% at five years. Moreover, liver
transplantation is the best option for patients with tumors that are less
than 5cm in size who also have signs of liver failure. In fact, as one would
expect, patients with small cancers (less than 3 cm) and no involvement of
the blood vessels do very well. These patients have a less than 10% risk of
recurrent HCC after transplant. On the other hand, there is a very high risk
of recurrence in patients with tumors greater than 5 cm or with involvement
of blood vessels. For these reasons, when patients are being evaluated for
treatment of liver cancer, every effort should be made to characterize the
tumor and look for signs of spread beyond the liver.
There is a severe shortage of organ donors in the U.S. Currently, there
are about 18,000 patients on the waiting list for liver transplantation.
About 4,000 donated cadaver livers (taken at the time of death) are
available per year for patients with the highest priority. This priority
goes to patients on the transplant waiting list who have the most severe
liver failure. As a result, in many HCC patients, while they are on the
waiting list, the tumor may become too large for the patient to benefit from
liver transplantation. Doing palliative treatments, such as TACE, while the
patient is on the waiting list for liver transplantation is currently being
evaluated.
The use of a partial liver from a healthy, live donor may provide a few
patients with HCC an opportunity to undergo liver transplantation before the
tumor becomes too large. This innovation is a very exciting development in
the field of liver transplantation.
As a precaution, doing a biopsy or aspiration of HCC should probably be
avoided in patients considering liver transplantation. The reason to avoid
needling the liver is that there is about a 1 to 4% risk of seeding
(planting) cancer cells from the tumor by the needle into the liver along
the needle track. You see, after liver transplantation, patients take
powerful anti-rejection medications to prevent the patient’s immune system
from rejecting the new liver. However, the suppressed immune system can
allow new foci (small areas) of cancer cells to multiply rapidly. These new
foci of cancer cells would normally be kept at bay by the immune cells of an
intact immune system.
In summary, liver resection should be reserved for patients with small
tumors and normal liver function (no evidence of cirrhosis). Patients with
multiple or large tumors should receive palliative therapy with
intra-arterial chemotherapy or TACE, provided they do not have signs of
severe liver failure. Patients with an early stage of cancer and signs of
chronic liver disease should receive palliative treatment and undergo
evaluation for liver transplantation.
It makes sense to screen for HCC just as we do for colon, cervical, breast,
and prostate cancer. However, the difference is that there is,
as yet, no cost-effective way of screening for HCC. Blood levels of
alpha-fetoprotein are normal in up to 50% of patients with small HCC.
Ultrasound scanning, which is non-invasive and very safe, is, as mentioned
before, operator-dependent. Therefore, the effectiveness of a screening
ultrasound that is done at a small facility can be very suspect.
Even more disappointing is the fact that no study outside of Asia has
shown, on a large scale, that early detection of HCC saved lives. Why is
that? It is because, as already noted, the treatment for HCC, except for
liver transplantation, is not very effective. Also, keep in mind that
patients found with small tumors on screening live longer than patients with
larger tumors only because of what is called a “lead time bias.” In other
words, they seem to liver longer (the bias) only because the cancer was
discovered earlier (the lead time), not because of any treatment given.
Nevertheless, strong arguments can be made for routine screening. For
example, the discovery of an HCC in the early stages allows for the most
options for treatment, including liver resection and liver transplantation.
Therefore, all patients with cirrhosis, particularly cirrhosis caused by
chronic hepatitis B or C, hemochromatosis, and alcohol, should be screened
at 6 to 12 month intervals with a blood alpha-fetoprotein and an imaging
study. I favor alternating between an ultrasound and CT scan (or MRI).
Patients with chronically (long duration) elevated alpha-fetoprotein levels
warrant more frequent imaging since these patients are at even higher risk
of developing HCC.
Fibrolamellar carcinoma is an HCC variant that is found in non-cirrhotic
livers, usually in younger patients between the ages of 20 and 40 years. In
fact, these patients have no associated liver disease and no risk factors
have been identified. The alpha-fetoprotein in these patients is usually
normal. The appearance of fibrolamellar carcinoma under the microscope is
quite characteristic. That is, broad bands of scar tissue are seen running
through the cancerous liver cells. The important thing about fibrolamellar
carcinoma is that it has a much better prognosis than the common type of
HCC. Thus, even with a fairly extensive fibrolamellar carcinoma, a patient
can have a successful surgical removal.
Worldwide, the majority of HCC is associated with chronic HBV infection.
Today, however, all newborns are vaccinated against hepatitis B in China and
other Asian countries. Therefore, the frequency of chronic HBV in future
generations will decrease. Eventually, perhaps in three or four generations,
HBV will be totally eradicated, thereby eliminating the most common risk
factor for HCC.
Some retrospective (looking back in time) studies suggest that patients
with chronic hepatitis C who were treated with interferon were less likely
to develop HCC than patients who were not treated. Interestingly, in these
studies, interferon treatment seemed to provide this benefit, even to
patients who had less than an optimal antiviral response to interferon.
Still, it remains to be seen whether the risk of developing cirrhosis and
HCC is significantly decreased in prospectively (looking ahead) followed
patients who responded to interferon.
One Japanese study has reported that a retinoid derivative (a compound
related to vitamin A) was effective in preventing recurrence of HCC after
resection of the liver. As of now, this compound is not available in the
U.S. It would be of great interest to study the use of this compound in
conjunction with other palliative therapy for HCC.
Treatment
Unfortunately, there have been no significant new developments in the
treatment of HCC. Medical therapy remains a disappointment. Scientists are
working hard, however, to address this problem. For example,
anti-angiogenesis compounds, which inhibit blood vessel formation, may hold
promise in the treatment of HCC since this tumor depends on a rich blood
supply. Also, different ways to deliver drugs or treatment to the tumors are
being investigated. This includes attaching radioactive material to
antibodies that are directed at specific targets in liver cancer cells
(immunotherapy).
HCC is the fifth most common cancer in the world and the majority of
patients with HCC will die within one year as a result of the cancer.
In the U.S., patients with associated cirrhosis caused by chronic
hepatitis B or C infections, alcohol, and hemochromatosis are at the
greatest risk of developing HCC.
Patients with chronic liver disease (e.g., HCV, HBV, or
hemochromatosis) should avoid drinking alcohol, which can further increase
their risk of developing cirrhosis and HCC.
Many patients with HCC do not develop symptoms until the advanced
stages of the tumor. When the patient does develop symptoms, the prognosis
is usually poor.
The combination of an imaging study (ultrasound, CT, or MRI scans) and
an elevated blood level of alpha-fetoprotein most effectively diagnoses
HCC.
A liver biopsy can make a definitive diagnosis of HCC, but the
procedure requires an expert liver pathologist and is not necessary for
all patients.
The natural history of HCC is quite variable, and depends on the stage
of the tumor and the severity of the associated cirrhosis.
Medical treatments for HCC, including chemotherapy, chemoembolization,
ablation, and proton beam therapy, are not very effective.
Surgical resection (removal) of the tumor may be very effective for a
select group of individuals with HCC, specifically for those with small
tumors and excellent liver function.
For patients with small HCC and significant associated liver disease,
liver transplantation offers the best chance for cure.
Medical Author: Tse-Ling Fong, M.D.
Medical Editor: Leslie J Schoenfield, M.D., Ph.D.
Patients with liver cancer can become viable candidates for transplantation
if their tumors respond to treatment, a new study suggests. This report is
in the September issue of Hepatology, a journal published by John
Wiley & Sons on behalf of the American Association for the Study of Liver
Diseases (AASLD). The article is available online at Wiley Interscience (http://www.interscience.wiley.com/).
For patients with liver cancer (also known as hepatocellular carcinoma),
transplantation has been restricted to those who fit the Milan criteria.
Their tumors must involve one lesion less than or equal to five centimeters
in diameter, or two to three lesions each less than or equal to three
centimeters. However, studies have suggested that patients with slightly
larger lesions may also do well with a transplant.
Rather than expand the Milan criteria, researchers have suggested
down-staging hepatocellular carcinoma to select for tumors with more
favorable biology that will respond to treatment and do well following liver
transplantation. The impact of successful down-staging on post-transplant
outcomes was heretofore unknown.
Researchers, led by Francis Yao of the University of California at San
Francisco, conducted a prospective study of down-staging protocol and report
intention-to-treat survival, dropout and post-transplant tumor recurrence,
along with factors that may influence response to down-staging treatment.
Between June 2002 and January 2007, the researchers enrolled 61 liver cancer
patients whose tumor stage exceeded the Milan criteria. Fifty-five of these
patients received a combination of laparoscopic radiofrequency ablation (RFA)
and transarterial chemoembolization (TACE). The remaining 6 patients
underwent resection as the down-staging procedure.
Down-staging was successful in 43 of the 61 patients (70.5 percent), and 35
of those received a liver transplant after a median of 8.2 months. While two
of the transplant recipients died (one from graft problems and the other
from recurrent hepatitis C infection), the remaining 33 were alive and free
of liver cancer recurrence after a median follow-up of 25 months.
In the patients for whom down-staging was unsuccessful, 15 had tumor
progression, while 3 died (two related to the down-staging, the other not.)
Comparing the clinical characteristics of the 35 patients who received a
liver transplant to the 18 patients with treatment failure, only median
alpha fetoprotein (AFP) level was significantly different. Treatment failure
was the eventual outcome in seven of the eight patients with pre-treatment
AFP > 1000 ng/mL. "High AFP may be a marker for vascular invasion or
extra-hepatic disease that escapes detection by conventional imaging
techniques," the authors suggest.
The authors note the heterogeneity of they loco-regional therapy may be a
weakness of their study, and that the optimal treatment should be determined
on a case-by-case basis. They also point out that 25 months of
post-transplant follow-up may be too short to fully determine the risk of
liver cancer recurrence.
Still, they conclude, "our results suggest that tumor down-staging to meet
conventional criteria for orthotopic liver transplantation (OLT) among
carefully selected patients is associated with excellent post-transplant
outcome. Down-staging put selection pressure against aggressive tumors that
are likely to progress despite treatment, whereas tumors with more favorable
histology are more likely to respond to treatment and do well after OLT."
They call for further studies to refine down-staging treatment strategies to
improve the intention-to-treat outcome.
---------------------------- Article adapted by Medical News Today from original press release.
----------------------------
Article: "Excellent outcome following down-staging of hepatocellular
carcinoma prior to liver transplantation: An intention-to-treat analysis."
Yao, Francis; Kerlan, Robert; Hirose, Ryutaro; Davern, Timothy; Bass,
Nathan; Feng, Sandy; Peters, Marion; Terrault, Norah; Freise, Chris; Ascher,
Nancy; Roberts, John. Hepatology; September 2008; 10.1002/hep.22412.
But a small
proportion of patients who achieve SVR may nevertheless develop
liver cancer, according to a report in the September 2008 Journal
of Viral Hepatitis.
Peter Ferenci and colleagues described 5 patients -- 3 from Austria,
2 from the U.S. -- who developed hepatocellular carcinoma during 3-6
years of follow-up after achieving SVR. All remained HCV RNA
negative during follow-up and at the time of HCC diagnosis. Three
patients did not have cirrhosis, either at the start of treatment or
at the time of liver cancer diagnosis. None had any other type of
liver diseases besides hepatitis C. One patient presented with
bilateral adrenal metastasis, while the remaining 4 had large liver
tumors.
"Successful antiviral treatment in HCV patients does not prevent
development of hepatocellular carcinoma even in non-cirrhotic
livers," the investigators concluded. "Long-term follow up of
patients with SVR is mandatory and should include surveillance for
hepatocellular carcinoma."
Department of Internal Medicine III, Division of Gastroenterology
and Hepatology, Medical University of Vienna, Vienna, Austria ; 2
Division of Gastroenterology, Department of Medicine, University of
Pennsylvania, Philadelphia, PA, USA ; and 3 Department of Clinical
Pathology, Medical University of Vienna, Vienna, Austria
10/10/08
Reference TM Scherzer, KR Reddy, F Wrba, and others. Hepatocellular
carcinoma in long-term sustained virological responders following
antiviral combination therapy for chronic hepatitis C. Journal of
Viral Hepatitis 15(9): 659-665. (Abstract).
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