liver cancer

WHAT IS LIVER CANCER (HEPATOCELLULAR CARCINOMA)?

A primary malignant liver tumor is a cancer that originates in the liver. The most common primary liver cancer in the world is known as hepatocellular carcinoma, also known as HCC or hepatoma. HCC is one of the most common cancers in the world, accounting for 6 percent of all cancers worldwide. Approximately 500,000 to one million cases of HCC occur each year. This makes HCC the fifth most common malignancy in men, and the ninth most common in women. Its greatest frequency occurs in Southeast Asia and Africa. Although its rate of occurrence has been rising over the past twenty years in the United States, it is still uncommon, accounting for only 0.5 to 2 percent of all cancers. The cause of this rise has been linked to the prevalence of chronic hepatitis C in the United States.

The characteristics of this cancer vary with geographic location. For example, in areas of the world where HCC is prevalent, such as in Asia and Africa, people are generally afflicted at an early age and often have a sudden onset of illness. In the United States, where this type of tumor is not as common, age of onset is generally at a later age and the tumor usually progresses slowly and silently. In general, men appear to be affected more frequently than women. In fact, in parts of the world where HCC is common, men are affected as much as eight times as frequently as women.

The following is a discussion of what causes HCC, what the associated symptoms and signs are, how a person is diagnosed, what the long-term prognosis is, and what some of the treatment options are for both operable and inoperable tumors.

The Causes of HCC

There is no simple explanation for why some people develop HCC and others do not. Most likely, there are multiple factors involved. The most significant known factor is the presence of cirrhosis due to any cause. Other factors may include genetic potential, hormonal influences, advancing age, state of general health and nutrition, lifestyle habits (especially alcohol abuse), and exposure to viruses and chemicals. While some of these factors are merely speculated to attribute to the development of HCC, other associations are definitively known. These specific factors are discussed below.

Cirrhosis

It is well established that there is a correlation between the presence of cirrhosis and the development of HCC. In fact, cirrhosis is present in approximately 60 to 90 percent of people with HCC. Furthermore, autopsy studies show that up to 28 percent of people with cirrhosis at the time of death also had HCC that went unrecognized during their lifetimes. In parts of the world where HCC is not very common, such as in the United States, cirrhosis is present in the vast majority of people with HCC. In contrast, in areas such as Mozambique, Africa, where 20 out of 100,000 people each year are afflicted with HCC, the association with cirrhosis, while common, is not as extensive This is probably due to the increased incidence in Africa of chronic hepatitis B - in which HCC may occur without cirrhosis, and the frequent consumption of foods contaminated with the liver toxic fungus-aflatoxin ( see page xx). Regardless of the geographic location, it does appear that repeated liver damage, independent of the cause of damage, can predispose the liver to abnormal cell growth, thereby resulting in HCC.

The risk of developing HCC in people with cirrhosis is between 1 and 6 percent per year. The risk of developing HCC differs somewhat depending upon the cause of cirrhosis. For example, people with chronic hepatitis B have a high risk of developing HCC in their lifetimes—up to 200 times the risk that the general population has. In contrast, the risk of HCC in a person with primary biliary cirrhosis, although present, is very low. For more information on cirrhosis, see Chapter 6.

Chronic Viral Hepatitis

People with either chronic hepatitis B (HBV)or hepatitis C(HCV) have an increased risk of developing HCC. However, since the genetic makeup of these viruses differs – DNA for HBV, and RNA for HCV, the mechanism of causing HCC also differs. The next few paragraphs discuss the relationship between these viruses and the development of HCC. See Part Two for a complete discussion of viral hepatitis, which includes chapters on each of the above-mentioned hepatitis viruses.

HEPATITIS B

There is a strong correlation between chronic hepatitis B and the development of HCC. Overall, HBV is responsible for approximately 75 percent of all HCCs. In fact, in countries with a high incidence of HCC, between 60 and 90 percent of people are found to have chronic hepatitis B. As previously noted, chronic hepatitis B infection can increase a person’s risk of developing HCC up to 200 times! Furthermore, HCC can occur in people with chronic hepatitis B even in the absence of cirrhosis. This may be partly due to an unidentified gene (HBx gene) that may make a person prone to developing HCC. Also, since hepatitis B is a DNA virus, it may actually incorporate its DNA into the DNA of the liver cells of the person it has infected. The mixing of genetic material from the hepatitis B virus and the patient may promote gene mutations leading to HCC even without underlying cirrhosis. The risk for a HBsAg carrier of developing HCC ranges from 0.06 percent to 6.6 percent each year. The risk increases with the severity of liver disease and the activity of the virus. Thus, those with cirrhosis and/or positive HBVDNA have the highest risk of developing HCC. Other risk factors for developing HCC include older age (greater than 40), male sex, and a family history of HCC.

While progression of disease is more rapid in people with both hepatitis B and hepatitis D, it is not clear whether these people who are doubly infected have a greater risk of developing liver cancer than those infected with HBV alone. In fact, some researchers believe that HDV may actually suppress the replication of HBV as some studies, have noted a reduced incidence of liver cancer in those who are doubly infected. Other researchers believe that if people infected with both HBV and HDV do not rapidly progress to liver failure then the risk of developing HCC may be quite high. More research needs to be done in this area before definitive conclusions about the interaction between these viruses can be drawn.

People doubly infected with both the hepatitis B virus (HBV) and the hepatitis C virus (HCV) do carry an increased risk of HCC. People with chronic hepatitis B who drink excessive amounts of alcohol have been found to develop HCC, on average, more than ten years earlier than those people who do not drink alcohol excessively. Therefore, people with chronic hepatitis B should avoid all alcohol as it can hasten progression to HCC.

It takes approximately twenty to thirty years for HCC to form in a person with chronic hepatitis B. Thus, people infected with the hepatitis B virus (HBV) at birth can develop HCC as early as twenty years of age, whereas people infected with HBV in adulthood tend to develop HCC in their sixties or seventies. The annual risk of developing HCC for people with chronic hepatitis B has been estimated to be between 0.5 and 3 percent.

HEPATITIS C

A strong correlation exists between chronic hepatitis C and the development of HCC. In contrast to hepatitis B, cirrhosis is present in all cases of hepatitis C-associated HCC. This is presumably because HCV is an RNA virus, and therefore cannot incorporate itself into the DNA of the person it has infected. There is increasing evidence that certain undefined HCV proteins may also contribute to the formation of HCC. People with hepatitis C who drink alcohol excessively appear to have a greater risk of developing HCC. This underscores the importance of total abstinence from alcohol in people with chronic hepatitis C. As stated above, it appears that coinfection with both HBV and HCV greatly increases a person’s chance of developing HCC. Therefore, obtaining the hepatitis B vaccination is crucial for people with hepatitis C who are not already infected with hepatitis B. (See Chapter 24 for more information on vaccinations.) It usually takes more than thirty years from the time a person becomes infected with HCV for HCC to develop. Once cirrhosis has developed it is estimated that there is a 1-6 percent chance each year for HCC to develop. It has been demonstrated that treatment with the drug interferon prior to the development of HCC actually lowers the incidence of HCC in some people with chronic hepatitis C. In fact, interferon treatment was found to be associated with a decreased risk of HCC even if the virus was not eradicated during therapy. This underscores the importance of early recognition and aggressive treatment of chronic hepatitis C in the early stages of disease- prior to the development of HCC.

Iron

As you learned in Chapter 18, iron is toxic to the liver. Iron can potentially cause gene mutations that may lead to HCC. Hemochromatosis is a genetically acquired liver disease of iron overload. While, by itself, hemochromatosis does not cause HCC, once it has progressed to cirrhosis, there is up to a 200-fold increase in the risk of developing HCC as compared with the general population. Phlebotomy helps prevent progression of disease. And, if started prior to the onset of cirrhosis, phlebotomy can help prevent the development of HCC in people with hemochromatosis. However, once cirrhosis has developed, the risk of developing HCC exists. This is true even if a person with cirrhosis has undergone successful phlebotomy. Once again, this demonstrates the importance of early recognition and treatment of liver disease.

Chronic Liver Disease

Autoimmune hepatitis, primary biliary cirrhosis, and nonalcoholic fatty liver disease are three other chronic liver diseases—discussed in Chapters 14, 15, and 16 respectively—that can lead to cirrhosis and thus to HCC. However, the incidence of HCC in these diseases is very low compared with the incidence of HCC in other chronic liver diseases, such as chronic hepatitis B, chronic hepatitis C, and hemochromatosis.

Lifestyle Factors—Alcohol Consumption and Cigarette Smoking

It is a well-known fact that alcohol can be toxic to the liver. In fact, most people associate the word cirrhosis with alcohol. Alcohol liver disease (ALD) is perhaps the most common cause of cirrhosis in the United States, and most cases of HCC in the United States are found in people with alcoholic cirrhosis. However, most research has shown that alcohol itself is not actually a direct cause of HCC. Rather, it is when alcohol causes liver damage and cirrhosis that HCC can develop. In people with either chronic hepatitis B or chronic hepatitis C, alcohol accelerates the course of the disease, leading to cirrhosis and HCC at an earlier age compared with people who do not drink alcohol. Thus, alcohol, in effect, acts as a co-carcinogen—a substance that, when combined with another carcinogenic factor, hastens the progression to cancer.

It is estimated that approximately 15 percent of people with alcoholic cirrhosis will develop HCC in their lifetimes. This percentage applies even to people who stopped drinking after they developed alcoholic cirrhosis. However, people with alcoholic cirrhosis who stop drinking live, on average, ten years longer than people with alcoholic cirrhosis who continue to drink. It is most likely that this increased survival time provides these people with an extra ten years in which to develop HCC. The close connection between alcoholic cirrhosis and HCC was underscored by an autopsy study performed on people who had alcoholic cirrhosis. Researchers discovered HCC in 55 percent of livers examined. A final note on this subject: People with any liver disease would be wise to abstain from alcohol due to the potentially toxic impact of alcohol on the liver.

The role of cigarettes in the development of HCC is not clear. However, some studies suggest that cigarette smoking may be a risk factor leading to HCC in some people with liver disease—especially those without evidence of chronic hepatitis B. Since cigarette smoking has been proven to be detrimental to health in so many ways, anyone who has liver disease is advised to not smoke cigarettes. This advice applies to all tobacco products.

Aflatoxin

Aspergillus flavus is a fungus (mold) that produces a toxic byproduct known as aflatoxin. Aflatoxin has been shown to be hepatotoxic (harmful or damaging to the liver) and to have the potential of leading to HCC. Foods stored in hot, humid conditions for prolonged periods of time are prone to mold and thus aflatoxin contamination. In certain parts of Africa, the incidence of HCC can be directly correlated with the amount of aflatoxin-contaminated food consumed. In parts of Africa and Asia, this fungus commonly poisons foods such as peanuts, soybeans, corn, and rice. Researchers have speculated that aflatoxin leads to liver cancer by causing a genetic mutation (mutation of the p53 gene). It is believed that aflatoxins may increase the toxic effect that hepatitis viruses have on liver cancer production; that is, it may act as a co-carcinogen. Aflatoxin contamination of foods is rare in the United States; therefore, aflatoxin is not considered to be a significant cause of liver cancer in the United States.

Drugs—Anabolic Steroids and Oral Contraceptives

Some people use anabolic steroids (muscle-building hormones) for medical reasons. Others use them to increase their competitive edge in sports. Men and women who take anabolic steroids for prolonged periods of time are at increased risk for the development of HCC. Therefore, unless there is a medical reason to use anabolic steroids, their use should be avoided.

Women who take oral contraceptives for a period of greater than eight years have a slightly increased risk of developing HCC. As noted on page XX, hepatic adenoma, which is associated with oral contraceptive use, has a small risk of developing into HCC.

Diabetes

Many researchers believe that diabetes may be a risk factor for HCC. This may be linked to elevated insulin levels in the blood ( hyperinsulinemia) that occurs in people with diabetes. It is believed that insulin activates certain factors that can cause gene mutations that lead to cancer. There is also increasing evidence that people with NASH (nonalcoholic steatohepatitis – chapter 16), many of whom have either diabetes and/or hyperinsulinemia, are at increased risk for progression to HCC. Finally, many people with type II diabetes are obese, and some researchers believe that obesity may be a risk factor for the development of HCC.

Gender and Race

Men are 2-4 times more likely to develop HCC than women. This is partly attributed to by the increased incidence of viral hepatitis and alcoholic cirrhosis in men. Hormonal factors- androgens, likely contribute to this increased incidence, but this association has not as yet been proven.

Within the United States, there are great differences among ethnic groups as to the incidence of HCC. Asians, Hispanics, and Native Americans are diagnosed with HCC almost three times more frequently than African Americans, who are diagnosed almost three times more frequently than Caucasians. These racial differences in HCC are most likely due to variations in time of acquisition of the liver disease, life style differences, and different incidences of HCV, HBV, and alcoholic cirrhosis among different ethnic groups. A specific ethnicity per se does not actually cause HCC.

Age

Gene damage and gene mutations may lead to HCC. As people age, there is an accumulation over time of gene damage due to a variety of factors. HCC is more frequently discovered as people age. In fact, it is rarely found in people under the age of 40. A major exception to this is in areas of the world where HBV is endemic ( i.e. sub-Saharan Africa and China). In these people HCC may occur as young as 20 years old.

The Symptoms and Signs of HCC

As previously noted, geography has considerable relevance to HCC. This relevance pertains to the rate of occurrence of HCC, as well as the array of symptoms associated with HCC. In areas with a low rate of occurrence of HCC, such as the United States, people with chronic liver disease or cirrhosis are more likely to be aware of their conditions and to be under a doctor’s care. In these people, HCC usually progresses slowly and silently, and symptoms experienced, if any, are those that pertain to cirrhosis. These people are usually detected to have HCC at a point when the tumor is quite tiny. Consequently, these people usually have no tumor-related symptoms at the time. This early detection of HCC is due to the fact that in the United States—as in many other developed countries—people with cirrhosis are commonly screened and monitored on a regular basis.

However, some individuals are first detected to have HCC when there has been an abrupt deterioration of an otherwise stable chronic liver disease course. Symptoms of HCC in these people can include abdominal pain, weight loss, fatigue, or manifestations of decompensated cirrhosis - such as encephalopathy (mental confusion). The liver is usually enlarged, rock hard, and nodular. Jaundice is present in some people, but is usually mild. Signs suggestive of cirrhosis may be present, or there may be obvious signs of decompensated cirrhosis, such as ascites (accumulation of fluid in the abdomen).

In contrast, in less developed areas of the world, such as sub-Saharan Africa, which has a high incidence of HCC, HCC is usually an aggressive disease with a rapid downhill course. These people are usually younger than those in geographic areas of low incidence and are often not aware that they have a chronic liver disease. These people often complain of sudden abdominal distention and tenderness, and a physical exam commonly reveals a mass in the right upper abdominal region. The doctor may hear a bruit over the liver during an exam. A bruit is a harsh, abnormal noise that can be heard through a stethoscope when it is placed over the liver. This is suggestive of a vascular tumor (a tumor that is chock full of blood vessels, such as HCC). Often, the initial complaint in these people is excruciating abdominal pain. Typically, the cause of this pain is that the tumor has ruptured. This is a medical emergency requiring immediate surgery. Low-grade intermittent fevers may also be present.

Some people will have symptoms of HCC that are exhibited in other organs of the body. This is due to secretion of substances, such as hormones, by the tumor to other parts of the body through the bloodstream. HCC-related symptoms, when manifested in other parts of the body are known as paraneoplastic syndromes. Paraneoplastic manifestations occur as one of the first symptoms of HCC in about 5 percent of people, although this percentage is higher for people in areas of high incidence of HCC. There are many types of paraneoplastic manifestations of HCC, but the two most common are a low glucose level (known as hypoglycemia), and a high cholesterol level (known as hypercholesterolemia). Less common manifestations include a high calcium level (known as hypercalcemia), an elevated red blood cell count (known as polycythemia), high blood pressure, signs of feminization in men, such as gynecomastia (breast enlargement), and watery diarrhea.

Diagnosing HCC

A person may be diagnosed with HCC through a combination of blood work, imaging studies, and liver biopsy. The following is a discussion of each of these diagnostic methods.

Blood Tests

In its earliest, most treatable stages, HCC can be very difficult to detect. Laboratory blood tests, such as those discussed in Chapter 3, may reveal few clues beyond an elevated AP or GGTP. Other blood test abnormalities, such as elevated liver enzymes or a decreased platelet count, are not due to HCC, but are due to the underlying liver disease, such as hepatitis or cirrhosis, respectively. Most of these tests are nonspecific and will give only vague hints that something more serious is wrong. Immediate suspicion for HCC should be raised when a person with a relatively stable course of liver disease abruptly develops a significant rise of liver function tests (LFTs). As emphasized throughout this book, the liver is a master of camouflage. Thus, a large tumor can be present in the liver despite minimal blood test abnormalities and a lack of symptoms. In fact, it is possible for more than half of one’s liver to be replaced by a tumor without causing significant blood test abnormalities or symptoms.

The only diagnostic test to detect HCC is a blood test known as alpha-fetoprotein (AFP). This test is one of the tumor markers (a blood test indicative of, but not diagnostic of, cancer). Normal adult level is less than 20 nanograms per milliliter (ng/ml). If the level in a person’s blood is over 400 ng/ml, then it is pretty safe to say that liver cancer is present. Levels under 400 ng/ml are a little more confusing. This is due to the fact that AFP levels can also be elevated as a result of many other conditions (see bulleted list below), especially any conditions in which there may be liver damage, such as cirrhosis or acute hepatitis. These other conditions rarely cause one’s levels to exceed 100 ng/ml. Recent studies have shown that AFP is less effective as a predictor of HCC in African Americans with hepatitis C than in other racial groups. Therefore, other methods of screening African American patients with HCV, such as a yearly MRI, should be considered.

Causes of an elevated AFP, other than HCC, include:

• Hepatitis—both acute and chronic

• Cirrhosis

• Liver metastases

• Pregnancy

• Cystic fibrosis

• Gastric cancer

• Pancreatic cancer

A rapidly rising AFP level, say from 60 ng/ml to 230 ng/ml within a few months—even if levels do not reach 400 ng/ml—is also suggestive of HCC. This abrupt increase signals the need to commence an intensive search for the tumor. It has been shown that initial AFP levels above 100 ng/ml in a person with chronic liver disease may foreshadow the development of HCC within the next five years. These people should be closely observed for tumor development. The degree of elevation of AFP is usually related to the size of the tumor—the larger the tumor, the higher the value. Thus, with very small lesions, AFP is often barely elevated.

After successful treatment of HCC, the level of AFP should normalize. It should rise again if there is a recurrence of the tumor. It can be seen that the AFP blood test is useful as a marker for the recurrence, as well as the initial detection of HCC. However, a person should not be lulled into a sense of total security if his AFP level is normal. Only about 67 percent of HCCs secrete AFP. This means that 33 percent of HCCs occur in people whose AFP is normal. Therefore, while this marker is very useful, it does have limitations.

Des-gamma-carboxyprothrombin (DCP), an abnormal form of prothrombin (a protein produced by the liver involved in blood clotting), is found to be elevated in 60 to 90 percent of people with HCC. DCP is positive even in some people with HCC whose AFP level is normal. However, DCP is rarely positive when HCC is less than 3 cm. in size. The accuracy of this blood test is presently being evaluated through research. If the statistical significance of DCP is confirmed, combined AFP and DCP blood tests will greatly improve the ability of physicians to detect HCCs.

Imaging Studies

One or more imaging studies (discussed in Chapter 3) are usually performed on people suspected of having HCC. The first is usually a sonogram. Tumors less than 2 centimeters in size (and possibly less than 1 centimeter in size) can be detected by this imaging study. Sonograms are the study most commonly recommended for HCC screening.

CT scan is often the next study obtained. A contrast dye is used to enhance the tumor, thus giving improved accuracy of diagnosis. A substance known as lipiodal, an iodinized poppy-seed oil contrast dye, is injected into the hepatic artery. This substance is promptly cleared from the rest of the liver, but remains in the HCC where it identifies abnormal tumor cells. HCC can be detected by a repeated CT scan performed about two weeks thereafter. Lipiodal creates an obvious contrast between normal tissue and the tumor. Tumors as small as 0.2 to 0.3 centimeters can be identified using lipiodal-enhanced CT scans.

MRI is also being used with increasing frequency to detect liver masses. It has an accuracy which is comparable to that of an enhanced CT scan. An enhancing substance, such as gadolinium, is used, as it improves diagnostic accuracy for some tumors by creating an identifiable contrast between normal tissue and a tumor.

Hepatic angiography is also used to aid in the detection of an HCC. It is the most invasive and expensive of all the imaging techniques, and it is used primarily to determine operability. In this technique, a catheter is placed into the hepatic artery and contrast-enhancing dye is introduced into the vessels that feed the tumor. A tumor is more vascular (contains an abundance of vessels) than the surrounding liver tissue, and vessels present in the tumor can be directly seen, thereby enabling the doctor to successfully locate the tumor.

Liver Biopsy

In cases where a tumor has been detected but the diagnosis is still in question, a liver biopsy is sometimes performed. The biopsy is usually performed by sonogram or CT scan guidance. Due to the fact that liver tumors are very vascular, the risk of bleeding increases. Also, there is a small risk of spreading the tumor along the track of the needle. Therefore, the use of a smaller –than-normal size needle is generally recommended. However, the tissue sample extracted using a small needle is often too small. Therefore, many times diagnostic uncertainties still cannot be resolved. Thus, for people with liver tumors, the role of liver biopsy is somewhat controversial. For a complete discussion of liver biopsies, see Chapter 5.

Screening and Surveillance for HCC

Screening and surveillance is done in order to detect HCC at an early enough stage so that surgery can either successfully remove the tumor in its entirety and thereby cure the condition or significantly improve the person’s chances for long-term survival. The importance of screening people who are at risk for liver cancer cannot be overemphasized. The chances of successful treatment are far greater when a tumor is detected in its earliest stages, as opposed to an advanced stage, where it may have already spread to other areas of the body. Anyone with cirrhosis from any cause and people with chronic hepatitis B (HBsAg positive) with or without cirrhosis are at risk of developing HCC. These people should be screened regularly for HCC. In this way, if a tumor forms, it is more likely to be detected in its earliest stages when it is most amenable to treatment.

While the exact method and interval of screening is subject to differing opinions, as a general rule, screening is advisable approximately every six months. This is based on the fact that the time it takes for HCC to double in size ranges from 1-19 months with a median time of 6 months. Screening is simple, quick, relatively inexpensive, and painless. It generally consists of a sonogram and the AFP blood test, and should be done at least once every six months. Diligent surveillance will detect approximately 25 to 65 percent of tumors at a size of 2 centimeters or smaller. Since, as previously noted, up to 37 percent of people with HCC will have normal levels of AFP it is important to use both screening methods for anyone who is at risk of HCC.

The Long-Term Prognosis for Those With HCC

When a small tumor (less than 5 centimeters) is detected by screening and surveillance techniques, there is a chance that it can be successfully removed in its entirety through surgery. Once the HCC has grown to greater than 5 centimeters, it is probably not curable, as it most likely will have already spread to other areas of the body (metastasized)—most commonly nearby lymph nodes and the lungs. For these people, some form of therapy (discussed on the following pages) should be initiated. Without therapy only 1 percent of these people will survive two years from the time HCC is detected.

Treatment Options for HCC

For people with HCC, prolonged survival is possible but in general, long-term prognosis is somewhat poor. The most common treatment options for HCC include surgical resection, liver transplantation, and the injection of alcohol directly into the tumor. Other options include tumor embolization, chemotherapy, hormonal manipulation, radiotherapy, and immunotherapy. Sometimes, a combination of these therapies will maximize results. At the end of 2007 a major advance occurred in the treatment of inoperable liver cancer - a drug called Nexavar was approved by the FDA. This drug, and all of these options will be discussed in more detail below.

Options differ greatly for those tumors that are surgically correctable (that is, single tumors and those less than 5 centimeters in size) as compared with tumors that are not amenable to surgery (that is, tumors at multiple sites in the liver and those that are greater than 5 centimeters in size or that have metastasized to other organs). The size of the tumor, the number of tumors present in the liver, and the status of the underlying liver disease are the important variables looked at when deciding which therapy would provide the best long-term results in each particular case.

Surgical Resection

Surgical resection (the removal of the tumor through surgery) is often the first option considered for people with HCC. In the absence of cirrhosis, up to 80 percent of a person’s liver can be removed, and the remainder will “regenerate” to its former full size, as discussed in Chapter 1. Surgical resection, performed on people who meet specific criteria, can potentially cure a person of HCC. The best candidate for surgical resection is a person with a solitary tumor less than 5 centimeters in size in a liver without cirrhosis. The tumor should also be isolated just to the liver and not have spread to other sites such as the lungs. Those who have an increased likelihood of positive results include people who are in otherwise good health and people younger than fifty years old. Unfortunately, only about 5 percent of all HCC diagnosed in the United States falls into these categories. Approximately half of those who undergo surgery will still be alive at least five years after surgery. The major disadvantage of surgical resection is that there remains a high risk of tumor recurrence because new tumors may develop in the remaining portion of the liver. And, if cirrhosis was initially present, overall liver function is not improved.

Liver Transplantation

Only approximately 30 percent of people with liver cancer have surgically resectable tumors at the time they are diagnosed. The remaining people must consider liver transplantation. Liver transplantation has the potential for removing from the body not only the tumor, but also any underlying cirrhosis. Thus, in people with a single HCC less than 5 cm in size, or in people with less than three HCC all less than 3 cm in size, liver transplantation is a good treatment modality. In such cases the 5 year survival time is 75 percent. Unfortunately, the waiting time for a liver transplant can make this option less effective. However, the newly implemented system for determining liver organ distribution – Model for Endstage Liver Disease (MELD), gives a higher priority to people with HCC. This will lessen the waiting time for people with HCC. Living donor transplantation in which part of the liver from a suitable donor (such as a relative or other person with the same blood type), is transplanted into the patient, is a particularly good option as it eliminates this delay. Some of the therapies used for inoperable tumors ( see below) may be used as an interim therapy for people awaiting a liver transplant. The topic of liver transplantation is discussed in further detail in Chapter 21.

Therapy for Inoperable Tumors

Due to the clandestine nature of liver disease, many tumors are already in advanced stages by the time they are recognized and, as such, are not amenable to any form of surgery. Some people are not candidates for surgery due to advanced age or poor general health. For these people, options include percutaneous alcohol injection, chemotherapy, radiation therapy, hormonal therapy, and gene therapy. The following is a discussion of these options.

Percutaneous Alcohol Injection (PEI). This therapy consists of a small needle being inserted percutaneously (through the skin) into the liver, much in the same manner as a liver biopsy is performed. The exact location of the tumor is pinpointed using a sonogram. Alcohol is then injected directly into the tumor through the needle. The alcohol acts to kill the cancer cells. The most common complaints concerning this procedure include mild pain and low fever, but otherwise it is well-tolerated. People who do best with this treatment are those who have a tumor smaller than 5 centimeters, those who have less than three tumors in the liver, and those who do not have advanced cirrhosis. In fact, up to 90 percent of small, solitary tumors -less than 3 centimeters in size, can be successfully killed using this method. Up to 70 percent of people whose tumors are eliminated are alive four years later. People with larger tumors or advanced cirrhosis do not have as high a success rate, and the incidence of recurrence of the tumor in these people is high, even when the original tumor was successfully killed using this method. For these people, other options are offered. These alternatives include combining PEI with chemoembolization (see below), the use of solutions other than alcohol (such as hot saline or acetic acid) for injection into the tumor, and even the placement of a microwave electrode directly into the tumor. The success rate, incidence of recurrence, and number of years of prolonged life applicable to each of these therapies is currently being reviewed by researchers. Although definitive numbers have not been established, some preliminary studies involving these treatments have shown positive results.

Tumor Embolization and Chemoembolization. When a cholesterol plac becomes lodged in an artery that leads to the heart, blood flow to the heart stops. This blockage of blood flow causes part of the heart muscle to die. This is commonly referred to as a heart attack or myocardial ischemia. Extrapolating this principle, if the hepatic artery (the artery that leads to the liver) is clogged, liver cancer cells may die. This deliberate clogging process is known as embolization. Substances that are used to block blood flow to liver cancer cells include gelatin-sponges (Gelfoam) and metallic coils. In many cases, anticancer drugs, such as doxorubicin or cisplatin, are introduced through the hepatic artery at the same time as Gelfoam or other substances. This is known as chemoembolization. This provides an increased concentration of the chemotherapy directly into the tumor—with less of the side effects of typical chemotherapy. While this treatment method does appear to reduce tumor growth, especially when lipiodal solution is added to the regimen, long-term survival is only slightly improved.

Other Options. Chemotherapy, using agents such as 5-fluorouracil, doxorubicin, or mitomycin, whether introduced as a single agent or in combination with each other, has not been found to significantly prolong survival.

Radiation therapy is used primarily to reduce pain associated with the tumor. Promising research is being conducted on proton irradiation and intraarterial irradiation, discussions of which are beyond the scope of this book.

Hormonal therapy using substances that inhibit both male and female hormones has been attempted. Anti-androgens (male-hormone inhibitors) have had poor results. Anti-estrogens (female-hormone inhibitors), such as tamoxifen, have shown promising results in some, but not all, studies. Research continues to be conducted in this interesting area.

Interferons are proteins made naturally in the body. They play an important role in regulating the immune system. It has been shown that they have both antiviral and anti-tumor properties. One group of researchers has demonstrated that the administration of interferon can prolong survival in people with inoperable HCC. Additional research will need to be done in this area before definite conclusions can be established. Interferon was discussed in more detail in Chapters 11, 12, and 13.

The freezing of liver tumor cells, also known as cryosurgery, is another technique being studied. Cryosurgery consists of destroying the tumor and surrounding liver tissue by injecting subzero liquid nitrogen into it. One drawback to this therapy is that it requires surgery. Another promising treatment involves the burning of liver tumor cells. This is known as thermal ablation and consists of transferring energy, in the form of radiofrequency waves, directly to tumor cells. One advantage to this technique is that no surgery is needed. Delivery of this thermal energy is via a needle inserted directly into the tumor under sonogram or CT-scan guidance. In this manner, liver tumor cells are killed by literally being “fried” to death. Both of these therapies take advantage of the fact that cancer cells are sensitive to temperature extremes.

Preliminary studies in Japan with polyprenoic acid, a form of vitamin A, appear promising. Also, vitamin K in combination with other forms of conventional treatment discussed on pages xx, may improve survival by preventing tumor extension into the portal vein.

Gene therapy, while still in experimental stages, is a promising new type of treatment for combating cancers. HCC seems to be well-suited to this treatment method, as some scientists believe that HCC involves a mutant gene—the p53 gene mutation. It is hoped that if the defective p53 gene can be replaced with a healthy copy of the p53 gene, the cancer process might be halted or even reversed.

Angiogenesis inhibitors are undergoing intensive research in mice. Angiogenesis is a term that means the development of new blood vessels. Just like all the organs in the body, cancers need a blood supply in order to live and grow. Angiogenesis inhibitors aim to block the signals that cancer cells release in order to entice new blood vessels. If this signaling process is blocked, tumor cells would die, as their blood supplies would be cut off. Thalidomide is an agent that has antiangiogenic properties. This medication was initially used to treat morning sickness in pregnant women. However, thalidomide was withdrawn from the market around 1961 due to its potential to cause severe birth defects – missing digits, arms and legs, in children whose mothers consumed it during pregnancy. Due to its antiangiogenic capabilities, thalidomide is now being used in experimental studies as a treatment for HCC. Preliminary results are encouraging.

NEXAVAR ( sorafenib)

A major advance in the treatment of inoperable liver cancer was the approval of Nexavar by the FDA on November 19, 2007. Nexavar is a 200 mg pill taken by mouth twice a day ( 2 tablets in the morning and 2 tablets at night on an empty tomach). It is known as a kinase inhibitor. Nexavar works by interfering with molecules that may be linked to sending mesages to cancer cells and by interfering in the formation of blood vessels that feed the cancer. Nexavar may also cause death of cancer cells. In clinical trials, patients who took Nexavar lived approximately 3 months longer than patients who took a placebo ( dummy drug), and the liver tumor grew much slower in the patients taking Nexavar. This result was considered to be so beneficial that the study was discontinued and Nexavar was granted FDA approval.

Side effects are manageable and include fatigue, weight loss, diarrhea and high blood pressure. Some patients developed a rash that consisted of skin shedding especially on their habds and feet, however, this side effect can be treated with special lubricating creams.

Nexavar is currently undergoing further studies for patients diagnosed with earlier stages of liver cancer.

Nexavar is co-manufactured by Bayer and Onyx Pharmaceuticals.

Melissa Palmer, MD is the author of " Dr. Melissa Palmer's Guide of Hepatitis and Liver Disease". (Published 2004. Penguin Putnam).

The office of Melissa Palmer, M.D. is located at:

1097 Old Country Road Suite 104

Plainview, Long Island N.Y. 11803

To arrange an appointment with Dr. Palmer, call

(516) 939-2626

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