Treatment of Liver Cancer

Early diagnosis and aggressive intervention are key to improving the prognosis of those diagnosed with liver cancer. Promising advances in the treatment of liver cancer are also giving patients new hope. Treatment of liver cancer is particularly challenging when compared with other types of cancer because in addition to the cancer itself, many patients have livers that have sustained damaged by chronic hepatitis B resulting in cirrhosis and various degrees of liver failure.

For each individual patient, the potential benefits of the various treatment options must be balanced with the risk of liver failure and how it affects the patient's quality of life.

Surgical Treatment

When the tumor is small or deemed surgically resectable, and the patient's liver condition is deemed fit for the planned resection, surgical removal offers the best chance for long-term survival. Despite complete removal of the tumor, patients are still at risk for recurrent disease, and they need to be followed closely long-term, especially during the first year when the risk of recurrence is greatest.

Nonsurgical Treatment

For patients who are not suitable resection candidates for anatomic or medical reasons, a number of treatment options, though limited in effectiveness, are available or being investigated in an attempt to control the disease long-term and with the aim of maintaining normal quality of life.

§  Traditional chemotherapy is generally ineffective, causes many side effects that may severely impair the patient's quality of life, and often does not prolong survival.

§  Intrahepatic arterial chemoembolization or chemoinfusion (TACE or TAC) has been adopted in the treatment of selected patients with unresectable lesions by the Stanford Multi-disciplinary Liver Tumor Clinic for the last four years. This treatment is not suitable for patients who already have signs of moderate liver failure and in patients with blockage of the portal vein. Long-term treatments with TACE or TAC have been associated with prolonged patient survival, and those who have good control or shrinkage of the tumor may even become suitable candidates for surgical resection or transplantation.

Liver Transplantation

Liver transplant is a treatment option for HCC that are surgically or medically unresectable, provided that the tumor is small (less than 5 cm or fewer than 4 lesions), confined to the liver, and without invasion into the blood vessels. More extensive tumors have a high risk for early recurrence and death after liver transplantation. After transplantation, the patient must receive either hepatitis B immunoglobulin (HBIG) or lamivudine, or both, to prevent HBV reinfection of the new liver.

Early diagnosis of small tumors is the only effective way of improving the outcome of liver cancer treatment, and that is only possible through screening of the high-risk population.

Liver Biopsy

A liver biopsy is a procedure that involves taking a small piece of tissue from the liver to examine under the microscope. A liver biopsy is ordered to detect potential liver damage caused by chronic hepatitis B infections. The results of a biopsy can be used to help in making treatment decisions or evaluating current treatment.

A liver biopsy is considered a minor surgical procedure that is done in the hospital, but does not usually require admission (it's done as an "out-patient procedure"). From check-in to check-out, patients should expect to be in the hospital for approximately  6 - 8 hours. Although the procedure itself is relatively short, there is a longer recovery period where they will be asked to lie on their right side for several hours to prevent any bleeding. Be sure to tell patients to arrange for someone to drive them home upon discharge.

Methods of Liver Biopsy

Needle Biopsy
Most patients undergo this type of liver biopsy. This procedure involves numbing an area on the right ribcage, making a tiny incision, and then inserting a thin needle between the ribs to obtain a small tissue sample from the liver (a ½ inch sample is removed).

Laparoscopic Biopsy
This procedure is ordered when tissue samples from specific parts of the liver are required. A special tube called a "laparoscope" is inserted through a small incision in the abdomen. The laparoscope sends images of the liver to a monitor that a doctor watches to guide him or her in obtaining tissue samples from one or more parts of the liver.

Tran venous Biopsy
This procedure is used when patients have blood-clotting problems or fluid in the abdomen. It involves placing a biopsy needle inside a tube called a catheter, which is inserted into a vein in the neck and then guided into the liver to obtain a tissue sample

Evaluation of Liver Cancer

Ultrasound of the liver and conventional CT scan are regularly obtained in the diagnostic evaluation of HCC (hepatocellular cancer or primary liver cancer), but they are often too insensitive to detect multi-focal small lesions and for treatment planning.

Thorough assessment with a biphasic spiral CT scan of the abdomen is essential. The fast spiral scanner allows scanning of the liver at the arterial phase shortly after the patient is given an intravenous bolus of contrast.

Percutaneous fine needle biopsy may be indicated in cases when the diagnosis of primary versus metastatic liver tumor is uncertain, providing that it can be safely performed. Post biopsy bleeding can be life threatening in cirrhotic patients with low platelet count, prolonged clotting time, and enlarged blood vessels that are under high pressure (portal hypertension). In general, metastatic liver lesions are rare in patients with cirrhosis. Screening for liver cancer is the only effective way of improving the outcome of treatment.

Liver Cancer Screening

Symptoms

Liver cancer is a silent killer because the majority of the patients appear to be perfectly healthy and have no early signs or symptoms. Pain is uncommon until the tumor is quite large, and some large tumors don't even cause pain or other symptoms.

Later stages of liver cancer, when the cancer is very large or when it impairs the functions of the liver, can produce more obvious symptoms such as pain over the right upper abdomen, weight loss, lack of appetite, and finally the development of yellow discoloration of the eyes and skin (jaundice) and abdominal swelling.

Screening Frequency

Hepatitis B carriers who become infected early in childhood have a high risk of developing liver cancer whether they have cirrhosis or not. The risk is greater in men and those with a positive family history for liver cancer.

A reasonable approach to liver cancer screening includes:

§Alpha-fetoprotein (AFP) blood test every 6 months

§Liver Ultrasound at least once or twice a year

Either test alone, however, can miss the diagnosis. Once the patient develops cirrhosis, more frequent screening is generally recommended. 

Hepatitis B and Primary Liver Cancer

Chronic hepatitis B infections cause 80% of all primary liver cancer worldwide.

Patients with chronic hepatitis B infections are at increased risk for progressing to liver cancer or hepato cellular carcinoma (HCC), whether they develop cirrhosis or not.

In the U.S. the overall incidence of cancer is decreasing, except for primary liver cancer (as reported by the National Cancer Institute in 2005). This is due in large part to the increased number of Americans who are chronically infected with hepatitis B and hepatitis C. Although survival rates for most types of common cancers have improved over the years, the 5-year survival rate for liver cancer is still below 10%.

In the world, primary liver cancer is the 3^rd leading cause of death. According to the World Health Organization, at least 550,000 people die each year from primary liver cancer.

The hepatitis B vaccine was named the first "Anti-Cancer Vaccine" vaccine by the U.S. Food and Dug Administration since it prevents hepatitis B infections, the leading cause of primary liver cancer.

Who should be screened for liver cancer?

Early detection improves the chances of survival after treatment. Since liver cancer develops quietly, usually without symptoms, patients with chronic hepatitis B should undergo regular liver cancer screening. A reasonable approach is to begin regular liver cancer screening at 30 years of age (although experts are recommending starting an even earlier age since liver cancer can strike children, though rare).

It is important to stress that Asians and Asian Americans, who generally develop chronic hepatitis B infections soon at birth, have a high risk of developing liver cancer at an early age whether they have cirrhosis or not. The risk is greater in men and those with a positive family history for liver cancer.

What is liver cancer screening?

This generally consists of a simple blood test for alpha-fetoprotein (AFP) levels every 6 months and an ultrasound of the liver at least once a year. Either test alone can miss the diagnosis. Some doctors prefer CT scans to ultrasounds. Once the patient develops cirrhosis, or has a family history of liver cancer, more frequent screening is generally recommended.

What are the symptoms of liver cancer?

Liver cancer is a silent killer because the majority of patients appear to be perfectly healthy and have no early signs or symptoms. Both small and large tumors may be undetected due to the shielded location of the liver underneath the ribs.

Pain is uncommon until the tumor is quite large, and some large tumors don't even cause pain or any symptoms. Later stages of liver cancer, when the cancer is very large or when it impairs the functions of the liver, can produce more obvious symptoms such as abdominal pain, weight loss, lack of appetite, and finally the development of jaundice and abdominal swelling.

How is liver cancer treated?

Treatment of HCC is particularly challenging when compared with other types of cancer because in addition to the cancer itself, many patients have livers that have been damaged by chronic hepatitis B infections. For each individual patient, the potential benefits of the various treatment options must be balanced with the risk of liver failure and how it affects the patient's quality of life.

Surgical Treatment - When the tumor is small and the patient's liver condition is stable, surgical removal offers the best chance for long-term survival. Despite complete removal of the tumor, however, patients are still at risk for recurrent disease. They will need to be followed closely long-term, especially during the first year when the risk of recurrence is greatest.

Nonsurgical Treatment - For patients who cannot undergo surgery, a number of treatment options, though limited in effectiveness, are available or being investigated in an attempt to control the disease long-term and with the aim of maintaining normal quality of life. Traditional chemotherapy is generally ineffective, causes many side effects that may severely impair the patient's quality of life, and often does not prolong survival.

TACE (or TAC) - Since HCC are hypervascular tumors often fed by one or more blood vessels from the hepatic arteries, they present the unique opportunity to target the therapy directly into the tumor. Intrahepatic arterial chemoembolization or chemoinfusion (TACE or TAC) is used in the treatment of selected patients with tumors that cannot be surgically removed.

Long-term treatments with TACE or TAC have been associated with prolonged patient survival, and those who have good control or shrinkage of the tumor may even become suitable candidates for surgical resection or transplantation.

What about a liver transplant?

Liver transplant is the only treatment option for patients with liver cancer tumors that cannot be surgically or medically removed. The tumor must be small (less than 5 cm or fewer than 4 lesions), confined to the liver, and without invasion into the blood vessels. Larger or more extensive tumors have a high risk for early recurrence after liver transplantation.

What does the future hold?

Early diagnosis of small tumors is the only effective way of improving the outcome of liver cancer treatment, and that is only possible through screening of the high-risk population. Universal hepatitis B vaccination is ultimately the only hope for reducing the incidence of this frequently fatal cancer worldwide.

Children with Chronic Hepatitis B

In general, the recommendations for children are the same as for adults - visits are typically every six months or once a year. Visits usually include a physical exam, HBV blood tests, AFP and LFT blood tests, and possible ultrasound imaging.

Adults with Chronic Hepatitis B

Six-month visits are standard, but more frequent visits may be required for some patients. Visits usually include:

§Physical exam

§Blood tests for hepatitis B markers

§Blood tests for LFTs and AFP

§Ultrasound imaging of the liver

Diagnosis and Management of Hepatitis B

High-Risk Groups

The hepatitis B virus can infect infants, children, teens and adults. Although everyone can be at some risk for a hepatitis B infection, there are people who are at greater risk because of their ethnic background, occupation, or lifestyle choices.

The following list is a guide for screening high-risk groups, but it certainly doesn't represent all potential risk factors.

§ Health care providers and emergency responders

§ Sexually active heterosexuals (more than 1 partner in the past six months)

§ Men who have sex with men

§ Individuals diagnosed with a sexually transmitted disease (STD)

§ Illicit drug users (injecting, inhaling, snorting, pill popping)

§ Sex contacts or close household members of an infected person

§ Children adopted from countries where hepatitis B is common (Asia, Africa, South America, Pacific Islands, Eastern Europe, and the Middle East)

§ Families of children adopted from the countries listed above

§ Individuals emigrating from countries where hepatitis B is common (see above)

§ Individuals born to parents who have emigrated from countries where hepatitis B is common (see above)

§ ALL pregnant women

§ Recipients of a blood transfusion before 1992

§ Kidney dialysis patients and those in early renal failure

§ Inmates of a correctional facility

§ Staff and clients of institutions for the developmentally disabled

§ Any individual who may have other risk factors not included on this list

Blood Tests

Be sure to carefully discuss your blood test results with your health care provider. Understanding your hepatitis B blood test results can be confusing, so you want to be clear about your diagnosis - do you have a new infection, have you recovered from a past infection, or do you have a chronic infection? 

You may want to take a copy of this information with you to your appointment to use as a reference guide. In addition, it is helpful if you request a written copy of your blood tests so that you fully understand which test is positive or negative.

To understand your tests, you will need to understand two basic medical terms:

§Antigen -a foreign substance in the body, such as the hepatitis B virus.

§Antibody -a protein that your immune system makes in response to a foreign substance.  Antibodies can be produced in response to a vaccine or a natural infection.  Antibodies usually protect you from future infection.

Common Hepatitis B Blood Tests

§HBsAg (hepatitis B surface antigen) - This refers to the outer surface of the hepatitis B virus that triggers an antibody response. A "positive" or "reactive" HBsAg test result means that the person is infected with the hepatitis B virus. This can be an "acute" or a "chronic" infection. Infected people can pass the virus on to others through their blood.

§HBsAb or anti-HBs (hepatitis B surface antibody) - This refers to the protective antibody that is produced in response to an infection. It appears when a person has recovered from an acute infection and cleared the virus (usually within six months) or responded successfully to the hepatitis B vaccine shots. A "positive" or "reactive" HBsAb (or anti-HBs) test result indicates that a person is "immune" to any future hepatitis B infection and is no longer contagious. This test is not routinely included in blood bank screenings.

§HBcAb or anti-HBc (hepatitis B core antibody) - This refers to an antibody that is produced in response to the core-antigen, a component of the hepatitis B virus. However, this is not a protective antibody. In fact, it is usually present in those chronically infected with hepatitis B. A "positive" or "reactive" HBcAb (or anti-HBc) test result indicates a past or present infection, but it could also be a false positive. The interpretation of this test result depends on the first two test results. Its appearance with the protective surface antibody (positive HBsAb or anti-HBs) indicates prior infection and recovery. For chronically infected persons, it will usually appear with the virus (positive HbsAg).

Hepatitis B Blood Tests: FAQ

Is there a blood test for hepatitis B?

There is a simple hepatitis B blood test that your doctor or health clinic can order called the “hepatitis B blood panel”. This blood sample can be taken in the doctor’s office. There are 3 common tests that make up this blood panel. Sometimes the doctor may ask to check your blood again six months after your first visit to confirm your hepatitis B status. If you think you have been recently infected with hepatitis B, it will take 4 -6 weeks before the virus will be detected in your blood.

Understanding your hepatitis B blood test results can be confusing, so you want to be clear about your diagnosis - do you have a new infection, have you recovered from a past infection, or do you have a chronic infection?  In addition, it is helpful if you request a written copy of your blood tests so that you fully understand which tests are positive or negative.

What three tests make up the "hepatitis B blood panel"? 

The hepatitis B blood panel requires only one blood sample but  includes three tests:

§HBsAg (hepatitis B surface antigen)

§HBsAb or Anti-HBs (hepatitis B surface antibody)

§HBcAb or anti-HBc (hepatitis B core antibody)

The doctor needs all 3 blood test results in order to determine your diagnosis.

What is the hepatitis B surface antigen (HBsAg)? 

These tests for the presence of virus. A "positive" or "reactive" HBsAg test result means that the person is infected with the hepatitis B virus, which can be an "acute" or a "chronic" infection. Infected people can pass the virus on to others through their blood and infected bodily fluids.

What is the hepatitis B surface antibody (HBsAb oranti-HBs)?

A "positive" or "reactive" HBsAb (or anti-HBs) test result indicates that a person has successfully responded to the hepatitis B vaccine or has recovered from an acute hepatitis B infection.  This result means that you are immune to future hepatitis B infection and you are not contagious. This test is not routinely included in blood bank screenings.

What is the hepatitis B core antibody (HBcAb)?

The HBcAb is an antibody that is part of the virus- it does not provide protection. A "positive" or "reactive" HBcAb (or anti-HBc) test result indicates a past or present infection, but it could also be a false positive. The interpretation of this test result depends on the results of the other two tests. Its appearance with the protective surface antibody (positive HBsAb or anti-HBs) indicates prior infection and recovery. For chronically infected persons, it will usually appear with the virus (positive HBsAg).

I donated blood and received a letter about hepatitis B from the blood bank, what does it mean?

First, do not panic. The letter does not necessarily mean that you are infected with hepatitis B. All donated blood is screened for hepatitis B. Many blood banks use the "hepatitis B core antibody" test to screen donor blood for potential hepatitis B infection (see “What is the hepatitis B core antibody?” above).  This test can detect whether a person might have been exposed to the hepatitis B virus, but by itself this blood test doesn't tell whether the person is actually infected or not. This is why it is very important to see your doctor so that he can order the hepatitis B blood panel to make an accurate diagnosis.

Understanding the Results of Your Blood Tests

The interpretation of each individual's results should receive expert evaluation. Unusual results do occur and the chart below is simply an "average" representing the most likely interpretation. It is not intended as personal medical advice. All individuals are strongly encouraged to consult their own health care provider to evaluate their blood test results.

Tests	Results	Interpretation	Recommendation
HBsAg	negative	Not immune - has not been infected, but is still at risk for possible future infection. Needs protection.	Get the vaccine.
HBsAb (anti-HBs)	negative
HBcAb (anti-HBc)	negative
HBsAg	negative	Immune - surface antibodies present. You may have been already vaccinated, or you have recovered from a prior hepatitis B infection. You cannot infect others.	The vaccine is not needed.
HBsAb (anti-HBs)	positive
HBcAb (anti-HBc)	negative or positive
HBsAg	positive	New infection or a chronic infection - positive surface antigen, which means hepatitis B virus is present. You can spread the virus to others.	Find a doctor who is knowledgeable about hepatitis B for further evaluation.
HBsAb (anti-HBs)	negative
HBcAb (anti-HBc)	negative or positive
HBsAg	negative	*Unclear- Several different interpretations are possible. You may need to have these tests repeated. See below.	The vaccine may or may not be needed. Find a doctor who is knowledgeable about hepatitis B for further evaluation.
HBsAb (anti-HBs)	negative
HBcAb (anti-HBc)*	positive

*Positive Hepatitis B Core-Antibody Test Result (HBcAB+)

1. May be recovering from acute hepatitis B infection
2. May be distantly immune and test is not sensitive enough to detect low level of HBsAb (or anti-HBs) in serum
3. May be susceptible with a false positive HBcAb or anti-HBc
4. May be undetectable level of HBsAg present in the serum and the person is actually chronically infected

Additional Blood Tests                                                         

HBeAg (Hepatitis B e-Antigen) - This is a viral protein that is secreted by hepatitis B infected cells. It is associated with chronic hepatitis B infections and is used as a marker of active viral disease and a patient's degree of infectiousness.

§A positive result indicates the person has high levels of virus and greater infectiousness.

§A negative result indicates low to zero levels of virus in the blood and a person is considered non infectious. This test is often used to monitor the effectiveness of some hepatitis B therapies, whose goal is to convert a chronically infected individual to "e-antigen negative".

The absence of e-antigen, however, does not necessarily exclude active viral replication. Some patient groups have mutant viruses that do not give rise to e-antigen. Patients with negative e-antigen, but detectable viral DNA, are traditionally thought to be more resistant to conventional treatment than those who have positive e-antigen levels.

HBeAb or anti-HBe (Hepatitis B e-Antibody) - This antibody is made in response to the e-antigen and is detected in patients who have recovered from hepatitis B infections as well as those who are chronically infected. Chronically infected individuals who stop producing e-antigen sometimes produce e-antibodies. The clinical significance of this result is unclear but it is generally considered to be a good thing. In rare cases, anti-HBe may be associated with active viral replication in patients with e-antigen negative virus mutations.

Liver Function Tests (or Liver Enzymes) - Includes blood tests that assess the general health of the liver. When elevated above normal values, the ALT (alanine aminotransferase) and AST (aspartate aminotransferase) tests indicate liver damage. They are enzymes located in liver cells that can leak out into the bloodstream when liver cells are injured.

§  ALT (alanine aminotransferase) is the liver enzyme marker that is followed most closely in those chronically infected with hepatitis B. This test is useful in deciding whether a patient would benefit from treatment, or for evaluating how well s/he is responding to therapy.

AFP (Alpha-FetoProtein) - This is a normal protein produced in the developing fetus. Pregnant women will have elevated AFP's. Other adults, however, should not have elevated AFP in their blood. This test is used as a liver tumor marker for patients with chronic hepatitis B. Patients should have their AFP levels monitored routinely since high levels could indicate the possibility of liver cancer.

Ferritin - Iron is stored in the liver in the form of ferritin. Increased levels of ferritin means a high level of iron is being stored. This could result from an increased iron intake in the diet (vitamin supplements, food cooked in iron pots, etc.), but it can also occur from a destruction of liver cells causing leakage of ferritin. More research is needed to understand the relationship between elevated ferritin and liver cancer.

A Guide to Common Blood Tests

Hepatitis B Basics and Beyond, Bristol-Myers Squibb Company Issue No. 2, October 2003

Test	Normal Range	Abnormal Range Mile-Moderate	Abnormal Range Severe
Liver Enzymes
Aspartate aminotransferase (AST)	<40 IU/L	40-200 IU/L	>200 IU/lL
Alanine aminotransferase (ALT)	<40 IU/L	40-200 IU/L	>200 IU/L
Gamma-glutamyl transferase (GGT)	<60 IU/L	60-200 IU/L	>200 IU/L
Alkaline phosphatase	<112 IU/L	112-300 IU/L	>300 IU/L
Liver Function Tests
Bilirubin	<1.2 mg/dL	1.2-2.5 mg/dL	>2.5 mg/dL
Albumin	3.5-4.5 g/dL	3.0-3.5 g/dL	<3.0 g/dL
Prothrombin time	<14 seconds	14-17 seconds	>17 seconds
Blood Count
White blood count (WBC)	>6000	3000-6000	<3000
Hematocrit (HCT)	>40	35-40	<35
Platelets	>150,000	100,000-150,000	<100,000
Key
U= International Unit	L=liter	dL=deciliter	mg=milligrams

Positive HBV Tests

An acute hepatitis B infection follows a relatively long incubation period - from 1 to 4 months. It can take up to six months, however, for a person's serology to reflect whether they have recovered from an acute infection or have become chronically infected.

The following graphic from the Centers for Disease Control and Prevention (CDC) represents the typical course of an acute hepatitis B infection.

CDC Notes About HBV Infections

Serologic markers of HBV infection vary depending on whether the infection is acute or chronic.

§HBsAg is the first serologic marker to appear following acute infection, which can be detected as early as 1 or 2 weeks and as late as 11 or 12 weeks (mode, 30-60 days) after exposure to HBV.

§HBsAg is no longer detectable in serum after an average period of about 3 months in persons who have recovered.   

§HBeAg is generally detectable in patients with acute infection; the presence of HBeAg in serum correlates with higher titers of HBV and greater infectivity.

§ A diagnosis of acute HBV infection can be made on the basis of the detection of IgM anti-HBc in serum; IgM anti-HBc is generally detectable at the time of clinical onset and declines to sub-detectable levels within 6 months.

§IgG anti-HBc persists indefinitely as a marker of past infection.

§HBsAb (or Anti-HBs) becomes detectable during convalescence after the disappearance of HBsAg in patients who do not progress to chronic infection. The presence of anti-HBs following acute infection generally indicates recovery and immunity from re-infection.

All patients with chronic hepatitis B infections, including children and adults, should be monitored regularly since they are at increased risk for developing cirrhosis, liver failure, or liver cancer.

Early intervention with the current treatments may benefit patients with signs of active liver disease. Screening and vaccination of family members is also recommended.