Leading the way to Treat Liver Cancer

Dr. Sukru Emre and Dr. Mario Strazzabosco, Leading
the way to Treat Liver Cancer December 6, 2009Welcome to Yale Cancer Center Answers with Drs. Ed Chu and
Francine Foss, I am Bruce Barber.  Dr. Chu is Deputy Director
and Chief of Medical Oncology at Yale Cancer Center and Dr. Foss is
a Professor of Medical Oncology and Dermatology specializing in the
treatment of lymphomas.  If you would like to join the
conversation, you can contact the doctors directly.  The
address is canceranswers@yale.edu and
the phone number is 1888-234-4YCC.  This evening Ed welcomes
Dr. Sukru Emre and Dr. Mario Strazzabosco.  Dr. Emre is a
Professor of Transplantation and Chief of Transplant Surgery at
Yale New Haven and Dr. Strazzabosco is a Professor of Internal
Medicine focused on Hepatology.Chu
 How many patients are diagnosed each year with this disease?Emre
 Liver cancer is a worldwide problem.  Its estimated mortality
annually is above 600,000 people worldwide.  The incidence
varies according to geographical areas and this is due to the
different incidence of the risk factors, of course.  So, if it
is extremely high in Asia and some parts of Africa and some
Mediterranean countries, it is less frequent in western countries
like the USA; however, it is rising even here.Chu             
 Mario, give us a sense of how many patients are diagnosed with
liver cancer in the United States?Strazzabosco
In the United States we have a mortality rate of 7,000 people per
year and a prevalence, which means the number of patients that are
sick, of 18,000, and in Connecticut, from were we speak, statistics
performed around five years ago show that there are at least 180
deaths per year due to liver cancer.Chu
 It's a pretty significant disease?Strazzabosco
It is indeed.Chu
 Sukru, there is now this appreciation that the incidence of liver
cancer, certainly here in the United States and I guess in some
other western countries, is steadily increasing. I know some of the
numbers that are projected out 10 to 15 years now are pretty
staggering, why is that?Emre
 Well the increasing number of persons living with cirrhosis is
likely the explanation for the increasing incidence of a
hepatocellular carcinoma resulting from a combination of factors,
including increasing incidence of cirrhosis caused by hepatitis C
cirrhosis, to a lesser extent hepatitis B infection, and general
improvement in survival among cirrhotic patients.  It has been
estimated that hepatitis C began to infect large numbers of young
adults in North America and South and Central Europe in the 1960s
and 1970s, as a result of intravenous3:10 into mp3 file 
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 drug use.  So the virus then moved into National blood
supplies and circulated until a screening test was developed in
1990.  After which time, rates of new infection decreased
dramatically.  Currently, it is estimated that a CV related
HCC will peak around the year 2010, next year.  If I
summarize, we are helping people survive hepatitis related
cirrhosis, that might be hepatitis C, hepatitis B, alcoholic liver
cirrhosis, or hemachromatosis, all these cirrhoses, whatever the
underlying etiology, sets the stage that the liver cells then can
change their regular rhythm, and then they develop cancer. 
So, since we are surviving longer we are going to see more and more
hepatocellular carcinoma.  One more thing I would like to say
here is that our estimate, after the diagnosis in cirrhosis in
hepatitis C patients, within five years approximately 25% to 30% of
patients will develop hepatocellular carcinoma.Chu
 Mario you had something to say?Strazzabosco
Sukru raised two very important points. In our countries, this
cancer rarely happens in patients without liver cirrhosis.  It
is mostly a consequence of chronic liver disease.
  And the second point that Sukru raised is that it takes a
long time to go from hepatitis to cirrhosis, to cancer, and we
estimate that this time can be between 20 and 30 years, and this is
why we are seeing now the cohort of patients that were infected 20
years ago before we started to use the interferon and other
antivirals, had the time to develop cirrhosis. This is why we
project that in the next 10 years the incidence will raise even
more.Chu
 Maybe we can just review for our listeners, what are the main
causes for chronic liver disease, cirrhosis that you talk about,
which then leads to liver cancer?Strazzabosco
Every kind of cirrhosis may ultimately lead to liver cancer,
although there are differences; some etiologies are more closely
related.  For example, the hepatitis B virus is a direct
oncogenic virus that can integrate into the DNA and favor the
expression of proto-oncogenes.Emre
 If I can add, in the United States and Europe the main reason is
hepatitis C, and in Asia and the southeast part of the world, it is
hepatitis B followed by hepatitis C, and other things such as
chemicals like alcohol and atrotoxin.  We do not see atrotoxin
related hepatitis HCC in this country, and also we have hormones
such as exogenous, steroidal sex hormones, and we have cirrhosis
related to metabolic diseases, such as tyrosinemia, such as primary
hemochromatosis, alpha 1 antitrypsin, and of course these diseases
will be effected and there are other factors modulating this such
as sex, such as age, and race that will be effecting the increasing
or decreasing the number of hepatocellular carcinoma cases.7:04 into mp3 file 
http://www.yalecancercenter.org/podcast/dec0609-treat-liver-cancer.mp3Chu
 For a long time it was felt that in this country, in the United
States, that alcohol-related liver disease, cirrhosis, was a main
reason for liver cancer, Mario your thoughts on that?Strazzabosco
As we said, all possible causes of liver disease, if left
untreated, will lead to cancer, but there is an important point to
make here that most often patients that progress to cirrhosis and
then to cancer have more than one risk factor, it is the
association of different risk factor that increases dramatically
the relative risk.  So, if you have hepatitis C and you do not
know it, and you drink socially and maybe you are overweight, your
risk of having the cancer increases dramatically.  If patients
acquired the virus when they maybe were using IV drugs when they
were younger and they have a co-infection, hepatitis B and C, even
if the hepatitis B has been longly nonactive, the risk of infection
increases dramatically. And now we have another player coming into
the game that surprises all of us, which is fatty liver and
steatosis, and Sukru and I are seeing more and more of this
patient.Chu
 And that is a consequence of obesity?Strazzabosco
Yes, of the metabolic syndrome.Emre
 That is correct.Chu
 In terms of age, what group is at highest risk for developing
liver cancer?Emre
 Based on our estimation, and as Mario indicated, that after
receiving or contracting the disease and viral diseases, the
development of cirrhosis, and for example, hepatitis C, takes
somewhere around 20 years, and after you develop cirrhosis,
development of HCC takes time, maybe five to seven years
more.  Thinking about just the development of cirrhosis, the
HCC takes 25 to 30 years.  If we assume that they contract the
disease somewhere in the teenage years, at 15 to 20 years of age,
our population is mostly somewhere between the 45 to 55 age range
where we are seeing the HCC more.Chu
 What are the typical symptoms associated with liver cancer, what
should people keep a look out for in terms of symptoms?Strazzabosco
Unfortunately, when you have symptoms related to liver cancer, your
cancer is very advanced, so what you should do is to take care of
your liver and your doctor should be able to identify the risk
factors that you may present, so the possibility of a cancer has to
be sought after, because if you can see the cancer when it is
small, there are many things that can be done.  If you wait
until the cancer causes portal vein thrombosis or
ascites…10:23 into mp3 file 
http://www.yalecancercenter.org/podcast/dec0609-treat-liver-cancer.mp3Chu 
             
 And ascites, can you define ascites for our audience?Strazzabosco
It is the presence of fluid in the peritoneal space in your
abdomen, outside of the abdomen.Chu
 So their belly would get a little bit bigger and
uncomfortable?Strazzabosco
Yes, there would be progressive increase of abdominal girth.Emre
 I would like to add a couple of things to what Mario said, it is
true that if cancer gives symptoms that means that it is very
extensive disease and there might be some dull abdominal pain,
sometimes we can see development of jaundice or a yellowing of the
eyes, and sometimes extreme pain can occur, and we do see ascites
or accumulation of the fluid in the abdominal cavity secondary to
the cirrhosis, not related to the hepatocellular carcinoma or liver
cancer, and if someone does not have a cirrhosis, the development
of ascites can be attributed to development of hepatocellular
carcinoma. The point we are making here, as Mario said, is we have
to look after these patients very carefully, monitor them, I am
talking about cirrhotic patients, because we do know that
sometimes, along the course of cirrhosis, they are going to develop
hepatocellular carcinoma. Screening programs are extremely
important in order to diagnose hepatocellular carcinoma early so
that we can do something about it before the cancer gets out of our
hands and spreads all over the body. That is our aim at this point
while we are dealing with cirrhotic patients, just to follow them
very carefully and probably every three to six months doing imaging
studies and sending what we call tumor markers, or alpha
fetoprotein, which is a specific tumor marker for hepatocellular
carcinoma, and if we see any imaging study inconsistent with
hepatocellular carcinoma, obtaining liver biopsies, and meanwhile,
we have different techniques that we are going to discuss later on,
to ablate these tumors or eradicate them that we can help them
survive for a longer time.Strazzabosco
There are actually some recommendations that have been developed by
the liver societies both in Europe and here, so if you know that
you have some of the risk factors, maybe you are infected with
hepatitis B, then you should look for the presence of liver cancer
by periodic imaging, even if you are not cirrhotic.  If you
have hepatitis C, or you are overweight, and you are drinking, then
your doctor should try to understand when and if your disease is
becoming chronic and cirrhotic, because from that point on, the
risk of developing a cancer is 5% per year; therefore, we do not
call it screening, but oncologic surveillance, at least with alpha
fetoprotein an ultrasound every six months is warranted.  That
is the only thing that will let you find the cancer still in a
treatable stage.Chu
 Time for us to break for a medical minute, you are listening to
Yale Cancer Center Answers14:02 into mp3 file 
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 and we are here in the studio this evening with doctors, Dr. Sukru
Emre and Dr. Mario Strazzabosco.Chu 
            
 Welcome back to Yale Cancer Center Answers, this is Dr. Ed Chu and
I am joined this evening by Dr. Sukru Emre and Dr. Mario
Strazzabosco from Yale Cancer Center. We are here talking about the
approach and treatment evaluation of patients with liver cancer,
and before the break we were talking about how important it is to
have very careful follow-up of patients who have chronic liver
disease. Mario, I will start with you, who would be the key person
to oversee the follow-up of a patient with chronic liver disease?
Is it a primary care physician, or would it be someone like
yourself who is a liver specialist, also known as a
hepatologist?Strazzabosco
This can be done by either.  The primary physician should know
that the patient with advanced liver disease should be screened
every six months for the presence of liver cancer, as we said
earlier, with an ultrasound of the abdomen and the liver and the
tumor marker which is called alpha fetoprotein.  However, I
would recommend sending to the hepatologist, patients that are
known to have liver disease, because we actually have designed our
practice and our clinic to care for this aspect.  It is
sometimes not very easy to understand when the moment is in which
chronic hepatitis actually becomes liver cirrhosis, which is
something much more severe, but can happen without any symptoms at
all.  Something changes in your liver and will not show
clinically for a long time, but the risk that comes with this
evolution, that may or may not happen, less than 20% of patients
that are infected with hepatitis C actually develop cirrhosis, so
there is a lot that your hepatologist or the primary care physician
can do before to prevent the cirrhosis and when you are cirrhotic
to understand what the risk is.17:04 into mp3 file 
http://www.yalecancercenter.org/podcast/dec0609-treat-liver-cancer.mp3Chu
 So once liver cancer is diagnosed, what is the process that is
involved in terms of staging the patient to see whether or not it
is local, confined to the liver, or has spread? What are the
different stages of liver cancer, maybe Sukru you can help us with
that?Emre
 When we diagnose the tumor, first of all the size of the tumor is
really important in order to stage the tumor, and the second thing
is the number of tumors. The third thing is whether the tumor is
opening to any major vessels, and we look at whether there is any
tumor outside of the liver and that includes lymph nodes around the
liver, bones, and the lungs, and we have to check whether they have
any lesions there or not.  So, based on looking at the size of
the tumor, we stage the tumors to four stages; stage I is tumor
less than 2 cm; and if there is more than one tumor and the size is
less than 3 cm, or one tumor size up to 5 cm, that will give us
stage II or T2 criteria; stage III may indicate that the cancer is
composed of several large tumors, or the cancer may be one large
tumor that has grown to invade the liver's main veins or to invade
nearby structures such as the gallbladder, and stage IV tumors
indicate that the liver cancer has spread beyond the liver to other
areas of the body.Chu
 Mario, what are the different treatment options that are available
to us once the liver cancer is diagnosed, once the staging
evaluation has been done?Strazzabosco
The treatment options actually depend strictly on the stage of the
tumor, and this is a very peculiar tumor, different from many
others, because it is a tumor in a failing organ.  There are
oncologic criteria and also functional criteria.  The liver of
the cirrhotic patient is not working very well, so that is a big
limitation to the amount of options that you have.  When we
stage the disease, we try to combine the oncologic extension of the
disease, which means size, number, metastasis, with the assessment
of liver function.  Every doctor who sees the patient with a
tumor would go through a mental flow chart. First of all he would
ask himself if this patient is cirrhotic, yes or no? And Sukru will
this explain later; there is a dramatic change in your option of
what to do. Secondly, can the tumor be resected by the surgeon? And
if not, what kind of alternative treatment can the patient
sustain?  And this really depends on the function of the
liver.  For example, you may have a small tumor that could be
addressed by different means, but in a patient with a functional
status that is so compromised your only option is actually to
transplant the liver.  On the other hand, you may have a
patient with a little bit of a larger tumor and of very well
preserved function, and this patient could be better served by
resection eventually or other intervention.  This is the
assessment that is made every time, and is an assessment that
requires multiple competences.  That is why all these patients
are discussed in a multidisciplinary board that includes
hepatologists, surgeons, transplant surgeons, surgical oncologists,
pathologists, and medical oncologists, all these specialties are
gathered and discuss the specifics of each case.21:58 into mp3 file 
http://www.yalecancercenter.org/podcast/dec0609-treat-liver-cancer.mp3Chu
 So at Yale, Sukru, just to expand a little bit, when you see a
patient newly diagnosed with liver cancer, you have this entire
team of doctors that Mario was discussing provide their individual
expertise, perspectives, and then come up with a game plan for the
patient?Emre
 That is right, to explain it a little bit more, at our
multidisciplinary liver cancer meeting, we have diagnostic
radiologists, interventional radiologists, hepatologists, and
 medical oncologists, surgeons, and social workers,
coordinators, and support staff as well, and we all meet
together.  Each case is discussed in detail and then options
are discussed, and if someone has very minimal liver reserve, and
the tumor is located in the middle of the liver, resection may not
be a good option.  On the other hand, if a patient has good
liver reserve, what we called Child A cirrhosis or compensated
liver cirrhosis, and a favorably located tumor, then resection
might be an option. The other option we should talk about is with
our interventional radiologists, and they do other ablation
techniques, one technique is called radiofrequency ablation, in a
way it's an ultrasound-guided approach and we get into the tumor
and we can create very high heat in the tumor and we can cook the
tumor, or we can freeze the tumor; these are different techniques.
Also, our interventional radiologists travel via the vessels and
they get into either the femoral vein, or arteries, then they
travel through the arteries and get into the arteries feeding the
liver, and even get close to the tumor, and we can deliver high
doses of chemotherapy in the tumor and then we knock down the
vessels, or arteries feeding the tumor, and we can shrink the tumor
down and keep the tumor in the liver.  This is a
multidisciplinary approach.Chu
 Sukru, since you are obviously an expert in liver transplantation,
when would you typically consider transplantation as a reasonable
treatment option for patients with liver cancer?Emre
 For transplantation there are two ways to look at it. If we have a
patient with a single tumor, we control this with ablation
techniques, and after ablation treatment, if there is no tumor in
the liver, there is no reason to transplant the patient. The second
issue is if there is a tumor in the liver and also there is
cirrhosis and liver disease, the organ allocation system in the
United States at this point allocates the organ based on the
severity of the liver disease.  Meanwhile, we develop some
rules for hepatocellular carcinoma, or liver cancer patients. 
If the cancer meets what we call T2 criteria, which I explained
before, and I will say it again, means that one tumor between 2 cm
to 5 cm, or up to three tumors less than 3 cm in diameter, then
those individuals will be assigned 22 MELD points then every
three months they accrue three more points, and eventually their
points will go 22, 25, 28, and 31, and they will get the liver
organ offers.  And I would like to say one thing that is
really important because it is very complex topic; organs are
allocated to patients directly based on MELD score.  MELD
stands for Medical End stage Liver Disease scoring system, so if
your liver tumor is more than the T2 criteria you may not get the
liver transplant through this system,27:04 into mp3 file 
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 for those cases, living donor liver transplantation will be a
great option for the patients and get the transplant done timely,
saving the life.Chu
 We have seen a lot of advances in the treatment of liver cancer
over the years, and Mario you have obviously been involved. In the
minute and a half we have left, can you tell us a little bit about
how things have evolved?Strazzabosco
This is an important question because it lets us also give some
good news to our patients. The treatment of liver caner has changed
dramatically in the last 10-15 years and what was previously a
death diagnosis, is now a diagnosis with which you can live many
years depending on the stage of the diagnosis of course, but we
also have multiple approaches. First of all, transplant is now an
option; it was not 10 year ago.  Second, our interventional
radiologist is continuously refining the approach that they can
offer to our patients and they can use embolization with
radioactive material, drug eluting beads, we do not have the time
to go into the details for each of those, and the last development
in the last two to three years has been the application of
biological drugs, meaning compounds that can block a specific
signaling mechanism that drives the growth of the tumor. 
There are many of these drugs in the pipeline as we say and will be
available to patients, and we put great hope in those new
non-chemotherapeutic oncologic drugs.Chu
 It is amazing how quickly the time has gone, and we will have to
have both of you come back so we can discuss more about how far we
have come in terms of treatment of patients with liver
cancer.  Thank you so much for joining us this evening. You
have been listening to Yale Cancer Center Answers and we would like
to thank our guests, Dr. Emre and Dr. Strazzabosco for joining us
this evening.  Until next time, I am Ed Chu from Yale Cancer
Center wishing you a safe and healthy week.If you have any questions or would like to share your
comments, you can go to yalecancercenter.org where you can also
subscribe to our podcast and find written transcripts of past
programs.  I am Bruce Barber and you are listening to the WNPR
Health Forum from Connecticut Public Radio.