Hepatocellular Carcinoma (Liver Cancer)

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Medical Author:

Keith E. Stuart, MD

Keith E. Stuart, MD

Dr. Keith E. Stuart is a medical oncologist specializing in the study and treatment of cancers involving the gastrointestinal tract, with a special interest in tumors involving the liver. He was educated at Harvard University (graduating magna cum laude) and Albert Einstein College of Medicine and did his medical training at the New England Deaconess Hospital.

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Medical Editor:

Melissa Conrad Stöppler, MD

Melissa Conrad Stöppler, MD

Melissa Conrad Stöppler, MD, is a U.S. board-certified Anatomic Pathologist with subspecialty training in the fields of Experimental and Molecular Pathology. Dr. Stöppler's educational background includes a BA with Highest Distinction from the University of Virginia and an MD from the University of North Carolina. She completed residency training in Anatomic Pathology at Georgetown University followed by subspecialty fellowship training in molecular diagnostics and experimental pathology.

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• What is liver cancer (hepatocellular carcinoma, HCC)?
• What is the scope of the liver cancer problem?
• What are the population characteristics (epidemiology) of liver cancer?
• What are liver cancer causes and risk factors?
• What are liver cancer symptoms and signs?
• How is liver cancer diagnosed?
• Blood tests
• Imaging studies
• Liver biopsy or aspiration
• What is the natural history of liver cancer?
• What are the treatment options for liver cancer?
• Chemotherapy and biotherapy
• Chemoembolization (trans-arterial chemoembolization or TACE)
• Radioembolization
• Ablation techniques
• Cryoablation
• Stereotactic radiosurgery
• Proton beam therapy
• Surgery
• Is there a role for routine screening for liver cancer?
• What is fibrolamellar carcinoma?
• What's in the future for the prevention and treatment of liver cancer?
• Liver Cancer At a Glance
• Patient Discussions: Liver Cancer - Diagnosis
• Patient Discussions: Liver Cancer - Describe Your Experience
• Find a local Oncologist in your town

The Relationship of Chronic Viral Hepatitis, Alcoholism, and Cirrhosis to Liver Cancer Medical Author: Jay W. Marks, MD Medical Editor: Leslie J. Schoenfield, MD, PhD Cancer can start within the liver (primary liver cancer or hepatocellular cancer) or spread to the liver (metastatic liver cancer) from other sites, such as the colon. Cancer that starts in the liver, which I will refer to simply as liver cancer, is the fifth most common cancer in the world. In the U.S., it is among the 10 most common cancers. This cancer is more frequent among Native Americans, Asians, Pacific Islanders, and Hispanics than among Caucasians. Liver cancer is a bad cancer. It has frequently spread beyond the liver by the time it is discovered, and only 5% of patients with liver cancer that has begun to cause symptoms survive even five years without treatment. The only hope for patients who are at risk for liver cancer is regular surveillance so that the cancers can be found early. Early cancers can be treated by surgical removal (resection), destruction of the individual tumors, or liver transplantation. Although the current techniques for surveillance are not very good at detecting early liver cancer, newer techniques are being tested and appear to be better. The most common diseases associated with liver cancer are chronic viral hepatitis, alcoholism, and cirrhosis (scarring of the liver). Moreover, chronic viral hepatitis is common in alcoholism, and both viral hepatitis and alcoholism cause cirrhosis which usually precedes the development of cancer. Therefore, the contributions and interrelationships of alcohol abuse, viral hepatitis, and cirrhosis in the development of liver cancer are complex. Despite the complexity, it is important to try to understand the contributions of each disease so that patients at highest risk for liver cancer can be targeted for surveillance. Theoretically, they also might be targeted with treatments that prevent the development of liver cancer, when such treatments are developed. Learn what puts you at risk for liver cancer » Top Searched Liver Cancer Terms: symptoms, tumor, transplant, treatment

What is liver cancer (hepatocellular carcinoma, HCC)?

Liver cancer (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 (for example, 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%-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. This is a much more common problem around the world than primary liver cancer and frequently leads to confusion, because 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 liver cancer.

What is the scope of the liver cancer problem?

Liver cancer is the third most common cancer in the world. A deadly cancer, liver cancer will kill almost all patients who have it within a year. In 2000, it was estimated that there were about 564,000 new cases of liver cancer worldwide, and a similar number of patients died as a result of this disease. About three-quarters of the cases of liver cancer are found in Southeast Asia (China, Hong Kong, Taiwan, Korea, and Japan). Liver cancer is also very common in sub-Saharan Africa (Mozambique and South Africa).

The frequency of liver cancer in Southeast Asia and sub-Saharan Africa is greater than 100 cases per 100,000 population. In contrast, the frequency of liver cancer in North America and Western Europe is much lower, less than five per 100,000 population. However, the frequency of liver cancer among native Alaskans is comparable to that seen in Southeast Asia. This reflects the prevalence of hepatitis B infection, which is the most common cause of this cancer worldwide. Recent data show, however, that the frequency of liver cancer in the U.S. overall is rising. This increase is due primarily to rising obesity and diabetes rates, and to chronic hepatitis C, another infection of the liver that causes liver cancer.

What are the population characteristics (epidemiology) of liver cancer?

In the U.S., the highest frequency of liver cancer occurs in immigrants from Asian countries, where liver cancer is common. The frequency of liver cancer among Caucasians is the lowest, whereas among African-Americans and Hispanics, it is intermediate. The frequency of liver cancer is high among Asians because liver cancer 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 (it is usually a childhood disease in Asia). 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 liver cancer. On the other hand, in Japan, North America and Europe, hepatitis C infection is a much more common cause; alcohol abuse is also an important contributing factor. All of these diseases cause continual damage to the liver, which can result in severe scarring (cirrhosis) that then can lead to cancer.

In areas where liver cancer is more common and associated with hepatitis B, the cancer usually develops in people in their 30s and 40s, as opposed to other areas of the world, where they are in their 60s and 70s. This is because it generally takes about 30 years of chronic damage to the liver before the cancer grows large enough to become obvious. Men are much more likely than women to have liver cancer, especially if they have hepatitis and cirrhosis. Regardless of the cause, patients with a history of alcohol abuse as well are much sicker when they initially develop the cancer. In North America, up to one-quarter of people with liver cancer have no obvious risk factors; they are generally healthier and do much better with treatment.

What are liver cancer causes and risk factors?

Hepatitis B infection

Hepatitis B can be caught from contaminated blood products or used needles or sexual contact but is frequent among Asian children from contamination at birth or even biting among children at play. The role of hepatitis B virus (HBV) infection in causing liver cancer is well established. Several lines of evidence point to this strong association. As noted earlier, the frequency of liver cancer relates to (correlates with) the frequency of chronic hepatitis B virus infection. In addition, the patients with hepatitis B virus who are at greatest risk for liver cancer are men with hepatitis B virus cirrhosis (scarring of the liver) and a family history of liver cancer. Perhaps the most convincing evidence, however, comes from a prospective (looking forward in time) study done in the 1970s in Taiwan involving male government employees over the age of 40. In this study, the investigators found that the risk of developing liver cancer was 200 times higher among employees who had chronic hepatitis B virus as compared to employees without chronic hepatitis B virus infection.

Studies in animals also have provided evidence that hepatitis B virus can cause liver cancer. For example, we have learned that liver cancer develops in other mammals that are naturally infected with viruses related to the hepatitis B virus. Finally, by infecting transgenic mice with certain parts of the hepatitis B virus, scientists caused liver cancer 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 hepatitis B virus cause liver cancer? In patients with both chronic hepatitis B virus and liver cancer, the genetic material of hepatitis B virus is frequently found to be part of the genetic material of the cancer cells. It is thought, therefore, that specific regions of the hepatitis B virus genome (genetic code) enter the genetic material of the liver cells. This hepatitis B virus 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 liver cancer that is associated with chronic hepatitis B virus occurs in individuals who have been infected most of their lives. In areas where hepatitis B virus is not always present (endemic) in the community (for example, the U.S.), liver cancer is relatively uncommon. The reason for this is that most of the people with chronic hepatitis B virus in these areas acquired the infection as adults, and very few develop an ongoing (chronic active) infection, which happens as often as 15% of the time in Asia.

Hepatitis C infection

Hepatitis C virus (HCV) infection is more difficult to get than hepatitis B. It usually requires direct contact with infected blood, either from contaminated blood products or needles. HCV is also associated with the development of liver cancer. In fact, in Japan, hepatitis C virus is present in up to 75% of cases of liver cancer. As with hepatitis B virus, the majority of hepatitis C virus patients with liver cancer 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 liver cancer after exposure to hepatitis C virus was about 28 years. The liver cancer occurred about eight 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 liver cancer in cirrhotic hepatitis C virus patients ranges from 1.4%-2.5% per year.

In hepatitis C virus patients, the risk factors for developing liver cancer include the presence of cirrhosis, older age, male gender, elevated baseline alpha-fetoprotein level (a blood tumor marker), alcohol use, and co-infection with hepatitis B virus. Some earlier studies suggested that hepatitis C virus 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 hepatitis C virus causes liver cancer is not well understood. Unlike hepatitis B virus, the genetic material of hepatitis C virus 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 liver cancer. Therefore, it has been argued that hepatitis C virus, which causes cirrhosis of the liver, is an indirect cause of liver cancer.

On the other hand, there are some chronic hepatitis C virus-infected individuals who have liver cancer without cirrhosis. So, it has been suggested that the core (central) protein of hepatitis C virus is the culprit in the development of liver cancer. 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 liver cancer in the developed world. In fact, at autopsy, as many as half of alcoholics previously unsuspected to have cancer will have early evidence of cancer hidden within the liver. Many of these people are also infected with chronic hepatitis C virus. The usual setting is an individual with alcoholic cirrhosis who has stopped drinking for 10 years and then develops liver cancer. It is somewhat unusual for an actively drinking alcoholic to develop liver cancer. 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 liver cancer after the drinking has been stopped.

More importantly, if an alcoholic does not stop drinking, he or she is unlikely to live long enough to develop the cancer. Alcoholics who are actively drinking are more likely to die from non-cancer related complications of alcoholic liver disease (for example, liver failure). Indeed, patients with alcoholic cirrhosis who die of liver cancer are about 10 years older than patients who die of non-cancer causes. Finally, as noted above, alcohol adds to the risk of developing liver cancer in patients with chronic hepatitis C virus or hepatitis B virus 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 liver cancer 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 liver cancer, but female hormones (estrogens) 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 diagnostic imaging studies, 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

Liver cancer will develop in up to 30% of patients with hereditary hemochromatosis (a disorder in which there is too much iron stored in the body, including in the liver). 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 liver cancer.

Diabetes and obesity

Over the past decade, the incidence of liver cancer in the United States has risen significantly, paralleling the rise in obesity. Although it is hard to separate the effects of diabetes from obesity on the liver, both conditions can cause chronic damage and accumulation of fat within the liver.. This is a disease called NASH (non-alcoholic steatohepatitis), which is present in up to 5% of North Americans. Fatty liver disease like this causes damage to the individual liver cells and may lead to cirrhosis in some people, thereby increasing the risk of liver cancer. Not only is the chance of developing the cancer enhanced, but patients with diabetes who undergo surgical removal of liver cancer have a higher chance of the cancer returning than do those without diabetes.

Cirrhosis

Individuals with most types of cirrhosis of the liver are at an increased risk of developing liver cancer. 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 liver cancer. 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 liver cancer than are other causes. For example, liver cancer 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 liver cancer is rarely found in primary biliary cirrhosis (PBC) as well. Recent studies, however, show that the frequency of liver cancer in PBC is comparable to that in other forms of cirrhosis.

What are liver cancer symptoms and signs?

The initial symptoms (the clinical presentations) of liver cancer are variable. It is becoming much more common for patients to be identified by screening people at high risk for the cancer and finding the cancer before there are any symptoms at all. In countries where liver cancer 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 liver cancer are generally developing countries where access to health care is limited. For another, screening examinations for patients at risk for developing liver cancer are not available in these areas. In addition, patients from these regions may actually have more aggressive liver cancer disease. In other words, the tumor usually reaches an advanced stage and causes symptoms more rapidly. In contrast, patients in areas of low liver cancer frequency tend to have liver cancer tumors that progress more slowly and, therefore, remain without symptoms longer.

There are no specific symptoms of liver cancer, and in fact, the earliest signs are usually subtle and can be mistaken for simple worsening of cirrhosis and liver function. Abdominal pain is uncommon with liver cancer and usually signifies a very large tumor or widespread involvement of the liver. Additionally, unexplained weight loss or unexplained fevers are warning signs of liver cancer in patients with cirrhosis. These symptoms are less common in individuals with liver cancer 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 liver cancer.

A common initial presentation of liver cancer in a patient with compensated cirrhosis (meaning that there are 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 (for example, alcohol consumption) suggests the possibility of liver cancer. 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. Liver cancers 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 liver cancer. Any sign of advanced liver disease (for example, ascites, jaundice, or muscle wasting) means a poor prognosis. Rarely, a patient with liver cancer 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 liver cancer, the tumor can spread locally to neighboring tissues or, through the blood vessels, elsewhere in the body (distant metastasis). Locally, liver cancer 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 distant metastases, liver cancer frequently spreads to the lungs, presumably by way of the bloodstream. Usually, patients do not have symptoms from the lung metastases, which are diagnosed by radiologic (X-ray) studies. Rarely, in very advanced cases, liver cancer can spread to the bone or brain. These are an infrequent problem in many patients who do not live long enough to develop these complications.

How is liver cancer diagnosed?

Blood tests

Liver cancer is not diagnosed by routine blood tests, including a standard panel of liver tests. This is why the diagnosis of liver cancer 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 liver cancer 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 liver cancer, this usually signifies extensive cancerous involvement of the liver. At that time, any medical or surgical treatment may be too late.

Sometimes, however, other abnormal blood tests can indicate the presence of liver cancer. 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 liver cancer, the cancerous liver cells may take on the characteristics of other types of cells. For example, liver cancer 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 (hypoglycemia) and high blood calcium (hypercalcemia).

Another abnormal blood test, high serum cholesterol (hypercholesterolemia), is seen in up to 10% of patients from Africa with liver cancer. 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 liver cancer. 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:

• Liver cancer
• 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 liver cancer can have mild or even moderate elevations of AFP.

The sensitivity of AFP for liver cancer is about 60%. In other words, an elevated AFP blood test is seen in about 60% of liver cancer patients. That leaves 40% of patients with liver cancer who have normal AFP levels. Therefore, a normal AFP does not exclude liver cancer. Also, as noted above, an abnormal AFP does not mean that a patient has liver cancer. It is important to note, however, that patients with cirrhosis and an abnormal AFP, despite having no documentable liver cancer, still are at very high risk of developing liver cancer. Thus, any patient with cirrhosis and an elevated AFP, particularly with steadily rising blood levels, will either most likely develop liver cancer or actually already have an undiscovered liver cancer.

An AFP greater than 500 ng/ml is very suggestive of liver cancer. In fact, the blood level of AFP loosely relates to (correlates with) the aggressiveness of the liver cancer. Finally, in patients with liver cancer 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 liver cancer is successfully removed surgically (resected). People with higher AFP levels generally do not live as long as those with lower AFP levels.

There are a number of other liver cancer 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 (for example, 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 liver cancer than with AFP alone.

Imaging studies

Imaging studies play a very important role in the diagnosis of liver cancer. 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 liver cancer. Further, there is no practical role for nuclear medicine scans of the liver and spleen in the workup for liver cancer. 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 liver cancer 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 liver cancer. But in these studies, highly experienced individuals performed the scans and spent up to one hour scanning each patient suspected of having liver cancer. 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 workup 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 liver cancer 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 liver cancer.

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 (for example, gadolinium).

MRI scans are 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. MRI sometimes finds lesions that are smaller than can be seen on a CT scan and can tell the radiologist more about the blood vessel (vascular) characteristics of the tumor; more importantly, there is no radiation risk, which becomes important if the screening test is to be repeated many times over a person's lifetime.

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 liver cancer shows a characteristic blush that is produced by newly formed abnormal small arteries that feed the tumor (neovascularization).

Another potential test used for many other cancers is a PET (positron emission tomography) scan, which involves the injection of radioactive sugar to light up actively growing cells, as in cancers. However, this is not very useful in liver cancer.

What, then, is the best imaging study for diagnosing liver cancer? There is no simple answer. Many factors need to be taken into consideration. For example, is the diagnosis of liver cancer 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, for example, apacemaker 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 multiphase 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.

Liver biopsy or aspiration

In theory, a definitive diagnosis of liver cancer 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 liver cancer and normal liver tissue. Also, some pathologists can mistake liver cancer 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 (liver cancer). Therefore, all of this considered, it is important that an expert liver pathologist review the tissue slides of liver tumors in questionable situations. New advances in immunohistochemistry (staining the microscopic cells with proteins that identify cell types very specifically) have helped to be able to tell the difference among cell and cancer types more reliably.

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 liver cancer is a tumor that is very vascular (contains many blood vessels). Extremely 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 is not generally recommended. 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.

All of that said, in many instances, there is probably no need for a tissue diagnosis by biopsy or aspiration. If a patient has a risk factor for liver cancer (for example, cirrhosis, chronic hepatitis B, or chronic hepatitis C) and a significantly elevated alpha-fetoprotein blood level, the doctor can be almost certain that the patient has liver cancer without doing a biopsy. Moreover, recent advances in MRI interpretation can identify small liver cancers as such with an extremely high degree of probability. However, recent understanding of gene variations in some liver cancers is beginning to be useful in helping to decide what kind of therapy might be best for an individual patient. Therefore, the patient and physician should always ask two questions before deciding on doing a liver biopsy:

1. Is this tumor most likely a liver cancer? 2. Will the biopsy findings change the management of the patient?

If the answer to both questions is yes, then the biopsy should be done. Finally, there are two other situations related to liver cancer in which a biopsy may be considered. The first is to characterize a liver abnormality (for example, a possible tumor) seen by imaging in the absence of risk factors for liver cancer or elevated alpha-fetoprotein. The second is to determine the extent of disease when there are multiple areas of abnormalities (possibly tumors) seen by imaging in the liver.

Overall, no blanket recommendation can be given regarding the need for liver biopsy or aspiration. The decision has to be made on an individual basis, depending on the treatment options and the expertise of the medical and surgical teams. The truth is, biopsies are not always definitive; people with cirrhosis have many small nodules in their livers, and while one might be cancerous, others are not. Occasionally, people have to undergo several biopsies over many months before a definite diagnosis can be made.

What is the natural history of liver cancer?

The natural history of liver cancer depends on the stage of the tumor and the severity of associated liver disease (for example, 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 three 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 six months, even with treatment.

What are the predictors of a poor outcome? Our knowledge of the prognosis is based on studying many patients with liver cancer, separating out their clinical characteristics, and relating them to the outcome. Grouped in various categories, the unfavorable clinical findings include the following:

• 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)
• Blood tests: elevated liver tests (bilirubin or transaminase), reduced albumin, elevated AFP, elevated blood urea nitrogen (BUN), or low serum sodium
• Staging of tumor (based on imaging or surgical findings): more than one tumor, tumor over 3 cm (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 liver cancer. 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 18 months. This kind of variability tells us that every patient with liver cancer is unique. Therefore, an assessment of the natural history and the evaluation of different treatments are very difficult. Nevertheless, in patients with a solitary liver cancer 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.

What are the treatment options for liver cancer?

The treatment options are dictated by the stage of liver cancer and the overall condition of the patient. The only proven cure for liver cancer is liver transplantation for a solitary, small (<3cm) tumor. Now, many physicians may dispute this statement. They would 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 liver cancer also have cirrhosis of the liver and would not tolerate liver resection surgery. In fact, in the United States, only 8% of people with liver cancer are able to undergo 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 liver cancer elsewhere in the liver within several years. In fact, some experts believe that once a liver develops liver cancer, 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). This makes sense, since whatever in the liver caused the cancer to develop in the first place is still there. Realistically, though, donor livers are a very limited resource, so many patients who need a transplantation will never receive one.

The results of the various medical treatments available (see below; 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.

One thing to keep in mind is that in a relatively healthy patient there is never just one answer to this question. Usually, people go through multiple different treatments sequentially. Something is chosen as the best place to start, and then other treatments are tried once the previous one stops working. The idea is to make sure someone is healthy enough to be able to try another therapy if they still desire it.

Chemotherapy and biotherapy

Systemic (entire body) chemotherapy

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 withtamoxifen (Nolvadex) but more studies show no advantage at all. Octreotide (Sandostatin) given as an injection was shown in one study to slow down the progression of large liver cancer tumors, but so far, no other studies have confirmed this benefit. Recent studies suggest that combinations of drugs such as gemcitabine, cisplatin, or oxaliplatin can shrink the tumors in some people.

Biotherapy

One of the most important recent advances in the filed of treating liver cancer has been the understanding of the genetic makeup of these tumors, as well as the cancer cells' reliance upon blood vessels and molecules produced in the body that can help them grow. Many cancers grow by causing the development and recruitment of tiny new blood vessels to feed the tumor and enable it to spread to other parts of the body. This is called angiogenesis, and this has become a very hot field in oncology and pharmaceutical development over the past decade. One drug, bevacizumab, has been approved for use in many cancers such as colon, lung, and breast, and is known to help standard chemotherapy shrink and control other types of cancer. It might be helpful in liver cancer as well, and similar drugs are still being investigated.

The best success so far has been with the oral drug sorafenib (Nexavar). This is a pill designed to block several components of the angiogenesis pathway, as well as other growth signals for individual cancer cells. Large studies have shown that patients taking this drug for advanced liver cancer live significantly longer than those taking a placebo pill. Although the difference was not very long (three months) and is shorter in sicker patients, this is still the first study in decades to show that there is a reliable way to slow down this cancer's growth and to prolong patients' lives. Sorafenib is thus the first, and so far, only, drug to be approved by the U.S. FDA to treat liver cancer. Current studies are under way to see if the drug works better when combined with other types of chemotherapy.

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, liver cancer 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). Liver cancer 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 six- to 12-week intervals. This procedure is done with the help of fluoroscopy (a 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 enzyme 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 six to 12 weeks to assess the size of the tumor in response to the treatment.
For more, please read the chemotherapyarticle.

Chemoembolization (trans-arterial chemoembolization or TACE)

This technique takes advantage of the fact that liver cancer 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 gel foam 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 bloodstream. 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. In fact, TACE originally grew out of the observation that patients undergoing intraarterial chemotherapy who accidentally had their catheters clotted off did better!

By relying upon blocking blood flow to the tumor, TACE will also cause some damage to the surrounding liver, and this is its primary limitation. Although the tumor may shrink up to 70% of the time, the associated liver damage can cause pain, fever, nausea, infection, fluid accumulation, and rarely, death. Nonetheless, TACE has been shown to be better than no treatment in several studies. There are newer techniques for delivering chemotherapy intra-arterially and blocking the blood vessels at the same time (microscopic drug-eluting beads); while the side effects seem to be less, it is not clear whether this method is more effective.

While TACE is not suitable for people with very sick livers or who are otherwise medically compromised, it is one of the most widely used techniques to control liver cancer around the world. It is important to realize, though, that it is not a cure and can only control the cancer for a limited time. However, in many individual patients appropriately chosen by their physicians, TACE can help to keep them alive longer.

Radioembolization

Radioembolization (also known as SIRT, or selective internal radiotherapy) involves attaching a radioactive molecule (called Yttrium) to tiny glass beads. These are then injected directly into the blood vessels feeding the cancers (as in TACE). The radiation particles can then kill tumor cells within a distance of 2.5 mm from them, so that any part of the cancer fed by tiny blood vessels will be exposed to the radiation. It seems to have fewer complications than TACE, although severe liver damage is still possible. The effectiveness is probably comparable to chemoembolization.

Ablation techniques

Ablation refers to any method that physically destroys a tumor, and is generally only applicable to situations in which there is only one, two, or sometimes three individual cancers in a liver. When there are more than that, it is not possible to reach every one on its own, so a different method such as systemic chemotherapy or TACE must be used.

Radiofrequency ablation (RFA) therapy

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. More commonly, the procedure is done without opening the abdomen by just using ultrasound or CT scan for visual guidance.

In RFA, heat is generated locally by high frequency radio waves that are channeled into metal 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 10-15 minutes. The whole procedure is monitored visually by ultrasound scanning. The ideal size of a liver cancer tumor for RFA is less than 5 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, which has been generally replaced by RFA, 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 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.

Cryoablation

Cryoablation is similar to RFA in that a single tumor is identified and then targeted by a radiologist with a needle inserted through the skin directly into the cancer. However, instead of using heat, cryoablation sues a probe filled with liquid nitrogen to freeze the tumor and kill it that way. This is probably as effective as RFA but can be used in some tumor locations where heat might accidentally damage adjacent organs (like when the gallbladder or colon is too close to the tumor).

Stereotactic radiosurgery

Stereotactic radiosurgery (SRS) is a new technique directing radiation (high-powered X-ray beams) directly to the tumor. Previously, radiation could not generally be used for liver cancer, because the normal liver was more sensitive to dying from radiation than the cancer was. SRS uses computer planning and CT scans to model the exact size, shape, and location of the cancer. It then directs the radiation machine, which can move around the patient in all three dimensions, to give many individual beams of radiation designed to converge just on the tumor, thus sparing much of the normal liver from the cumulative high doses. This appears to be very effective against solitary tumors.

Proton beam therapy

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 liver cancer. The ideal patient is one with only a small (<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 (for example, proton beam and TACE). Decisions are generally made by a multidisciplinary team of liver cancer specialists who are knowledgeable and expert in all of these techniques, so that the team can choose the best method for an individual patient depending upon overall health and liver function as well as the size, number, and location of the tumors.

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 (3 cm or less) tumors and excellent liver function, ideally without associated cirrhosis. As a result of these strict guidelines, in practice, very few patients with liver cancer 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 liver cancer, 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 rate is up to 60%. This means that 60% of patients who actually undergo liver resection for liver cancer are expected to live five years. Many of these patients, however, will have a recurrence of liver cancer elsewhere in the liver. Still, this is the procedure of choice for patients without cirrhosis and a solitary tumor who are felt to be medically able to undergo surgery.

Liver transplantation

Liver transplantation has become an accepted treatment for patients with end-stage (advanced) liver disease of various types (for example, chronic hepatitis B and C, alcoholic cirrhosis, primary biliary cirrhosis, and sclerosing cholangitis). Survival rates for these patients without liver cancer 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 5 cm 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 liver cancer 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. A recent change in distribution rules made liver cancer of under 5 cm a priority, so these people can spend less time on the waiting list. A newer, growing option is live donor transplantation.

The use of a partial liver from a healthy, live donor may provide patients with liver cancer 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 liver cancer should probably be avoided in patients considering liver transplantation. The reason to avoid needling the liver is that there is about a 1%-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. It now appears that people who do undergo transplantation for liver cancer have a lower chance of having the cancer return if they are first treated with a local method such as chemoembolization. This also helps them to be treated while they are spending time on the transplant waiting list, so that the cancer does not grow while they are waiting.

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 systemic 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 with RFA, cryoablation, or TACE and undergo evaluation for liver transplantation

Is there a role for routine screening for liver cancer?

It makes sense to screen for liver cancer 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 liver cancer. Blood levels of alpha-fetoprotein are normal in up to 50% of patients with small liver cancer; among native Alaskan women who have a high risk of liver cancer, the most common cause of an elevated AFP was pregnancy. Ultrasound scanning, which is noninvasive 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 liver cancer saved lives. Why is that? It is because, as already noted, the treatment for liver cancer, 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 a liver cancer 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, as well as some rarer diseases, are usually screened at six- to 12-month intervals with a blood alpha-fetoprotein and an imaging study. I favor alternating between an ultrasound and MRI. Patients with chronically (long duration) elevated alpha-fetoprotein levels warrant more frequent imaging since these patients are at even higher risk of developing liver cancer.

What is fibrolamellar carcinoma?

Fibrolamellar carcinoma is a liver cancer variant that is found in non-cirrhotic livers, usually in younger patients between 20 and 40 years of age. 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 liver cancer. Thus, even with a fairly extensive fibrolamellar carcinoma, a patient can have a successful surgical removal.

What's in the future for the prevention and treatment of liver cancer?

Prevention

Worldwide, the majority of liver cancer is associated with chronic hepatitis B virus infection. Today, however, all newborns are vaccinated against hepatitis B in China and other Asian countries. Therefore, the frequency of chronic hepatitis B virus in future generations will decrease. Eventually, perhaps in three or four generations, hepatitis B virus will be totally eradicated, thereby eliminating the most common risk factor for liver cancer. Studies have already shown a decrease of up to 75% in the incidence of liver cancer in children and teenagers in Hong Kong and even in the United States since routine vaccination was introduced.

Some retrospective (looking back in time) studies suggest that patients with chronic hepatitis C who were treated with interferon were less likely to develop liver cancer 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 liver cancer is significantly decreased in prospectively (looking ahead) followed patients who responded to interferon.

Theoretically, we know that liver cancer should be an almost totally preventable disease. Most of it is caused by infection with hepatitis; this can be reduced (if not eliminated) by treating infected mothers before they give birth, vaccinating all children regardless of where they live, screening the blood supply to avoid infected transfusion, and always using clean needles for any injections. (Many cases of hepatitis C infection are thought to have been from doctors or schools using the same needles for many patients or classroom vaccinations!) Aflatoxin contamination can be eradicated by proper storing of foodstuffs and, in fact, is not a measurable problem in developed countries. Alcohol abuse is difficult to eliminate, but at an individual level, this is a totally avoidable risk factor for liver cancer. Even more difficult is obesity and diabetes, but as with alcohol, personal lifestyle choices will directly lead to the development of this cancer. Therefore, a combination of societal, financial, and political changes around the world could lead to a very substantial decrease in the incidence of this cancer over the next two to three decades.

Treatment

Treatment options for liver cancer have grown exponentially over the past two decades. Using the way the cancer grows -- generally just within the liver, killing the person as it destroys the liver around it -- has led to many effective methods of attacking the cancer directly, through surgery, transplantation, ablation, and chemoembolization. In fact, the chances of someone with liver cancer being alive after just a year are now three times higher than they were 20 years ago, probably just because of the growth in popularity and effectiveness of these local treatment methods. The approval of sorafenib, the first drug shown to prolong lives in liver cancer, heralds a new understanding of the molecular nature of this cancer and has tremendously increased the interest of researchers and pharmaceutical companies in finding a more effective treatment for liver cancer. There is more research going on than ever before for these patients, and everyone should be encouraged to join a clinical trial if possible, to try to get the most advanced treatment available.

Liver Cancer At a Glance

• Liver cancer is the third most common cancer in the world, and the majority of patients with liver cancer 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, obesity or diabetes, and hemochromatosis are at the greatest risk of developing liver cancer.
• Patients with chronic liver disease (for example, hepatitis C virus, hepatitis B virus, or hemochromatosis) should avoid drinking alcohol, which can further increase their risk of developing cirrhosis and liver cancer.
• Many patients with liver cancer 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 liver cancer.
• A liver biopsy can make a definitive diagnosis of liver cancer, but the procedure requires an expert liver pathologist and is not necessary for all patients.
• The natural history of liver cancer is quite variable and depends on the stage of the tumor and the severity of the associated cirrhosis.
• Medical treatments for liver cancer such as chemotherapy are slowly becoming more effective, although still disappointing. The new drug sorafenib has shown that survival can be prolonged.
• Ablative and local techniques such as chemoembolization, radioembolization, radiofrequency or cryoablation, and stereotactic radiosurgery can by very useful in controlling individual cancers for an extended time.
• Surgical resection (removal) of the tumor may be curative for a select group of individuals with liver cancer, specifically for those with small tumors and healthy liver function.
• For patients with small liver cancer and significant associated liver disease, liver transplantation offers the only chance for cure.
• This is a disease that should be almost entirely preventable by societal and lifestyle changes.

Additional resources from WebMD Boots UK on Liver Cancer

Previous contributing author and editor:

Medical Author: Tse-Ling Fong, MD
Medical Editor: Paul Oneill, MD, Board Certified Oncology

REFERENCES:

Brown DB, Geschwind JF, Soulen MC, Millward SF, Sacks D. Society of Interventional Radiology position statement on chemoembolization of hepatic malignancies. J Vasc Interv Radiol. 2006 Feb;17(2 Pt 1):217-23.

Bruix J, Sherman M; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005 Nov;42(5):1208-36.

Garden OJ, Rees M, Poston GJ, Mirza D, Saunders M, Ledermann J, Primrose JN, Parks RW. Guidelines for resection of colorectal cancer liver metastases. Gut. 2006 Aug;55 Suppl 3:iii1-8.

Previous contributing medical editor: Leslie J. Schoenfield, MD, PhD

Last Editorial Review: 9/16/2011


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