Liver Cancer

The liver plays a vital role in maintaining the body's overall health.

The liver is a large organ located in the upper right side of the abdomen, where it is found mostly underneath the ribs. It plays a very important role in maintaining the body's overall health.

• Most of the blood leaving the intestines travels through the liver, where it is filtered of both toxic chemicals and bacteria.
• The liver uses nutrients in the blood to provide energy for the body by storing and releasing sugars.
• It is also the main source of proteins necessary for many bodily activities such as normal blood clotting, growth, and nutrition.
• In addition, the liver creates bile, a fluid that is important for digestion. It is made by liver cells called hepatocytes and is then carried in tubes (the bile ducts) directly into the intestine or into the gallbladder, where it is stored until we eat. When these tubes are blocked for some reason, the bile backs up into the bloodstream, causing a yellow tinge to the eyes, mouth, and skin, and darkening of the urine; this is called jaundice.

Picture of a hepatoma removed surgically, with surrounding normal liver.

Usually, when people speak of liver cancer, they mean cancer that has begun somewhere else in the body and then spread to the liver. This is called a secondary or metastatic disease or liver metastases. Due to its very high blood flow, as well as other factors still poorly understood, the liver is one of the most common places for metastases to take root. Tumors that originally arise in the colon, pancreas, stomach, lung, breast, or elsewhere can spread through the bloodstream to the liver, and then present as liver metastases. These metastases sometimes cause pain or damage liver function. In the Western Hemisphere, most cases of "liver cancer" actually are secondary, or metastatic cancers that started in another organ.

Sometimes, cancer may arise in the cells of the liver itself. Cancer of the hepatocytes (the main functioning liver cell) is a primary liver cancer called hepatocellular carcinoma or hepatoma. Hepatoma usually grows in the liver as one or more round tumors, invading and destroying the normal tissue as it expands. Such primary liver cancer can also spread to other parts of the body including the lungs and lymph nodes. Within the liver, cancer can also arise from the tubes that carry the bile. These bile duct cancers called intrahepatic cholangiocarcinoma are less common than hepatoma and hard to detect. Today's discussion will focus on hepatocellular carcinoma or hepatoma.

Most people who develop hepatoma have a liver that has already been damaged in some way, usually many years earlier. The most common risk factor in the United States is alcohol abuse; in the rest of the world, hepatitis B and hepatitis C are the risk factors responsible for most cases of hepatoma. Although these are preventable problems, the incidence of hepatoma is actually rising in many countries. In the United States, due in part to a large increase in hepatitis C infection several decades ago, the incidence has doubled to over 30,000 cases each year. Recent research has demonstrated that a part of the increase in hepatoma is due to the rise in obesity and diabetes over the past few decades, both of which can result in chronic fatty liver disease which can also damage the liver. Certain genetic diseases, such as hemochromatosis (a disease that results in abnormally high stored levels of iron), can also eventually result in the development of this tumor, as can aflatoxin, a food contaminant that is common in Africa and Southeast Asia.

Alcohol abuse: Those with a history of alcohol abuse have about a 15% lifetime chance of developing hepatoma, and it is frequently found unexpectedly at autopsy in alcoholics who die from other causes. The risk rises with increasing alcohol use but only up to a certain point; severe alcoholics will not live long enough to develop cancer, and because of this, the risk actually rises after quitting drinking.

Hepatitis B: This DNA virus is the most common cause of hepatocellular cancer worldwide, responsible for most cases of hepatoma in geographic areas where it is a very common cancer (Asia and sub-Saharan Africa). Many people in these parts of the world get infected with the virus at a young age, and 15% are unable to clear the virus from their systems. This leads them to become "chronic carriers," which increases the risk of developing hepatoma 200 times higher than normal. Along with steady and repeated destruction of the liver cells, the virus transfers some of its DNA into the human liver cells, and this helps initiate the process of transforming to a cancer cell (carcinogenesis).

Hepatitis C: This is an RNA virus, causing millions of infections over the past few decades by contaminated needles or blood products before a screening test was developed. This infection is responsible now for about three-quarters of all hepatomas in Japan and Europe. After infection, there is a lifetime risk of 5% of developing hepatoma, at an average time of 28 years after infection.

Aflatoxin: This is a byproduct of a mold affecting spoiled stored food products such as grains and peanuts in parts of the world such as Africa, Thailand, and the Philippines. Aflatoxin binds to the DNA of live cells and causes mutations that lead to cancer. This was the first discovery of precisely how an environmental contaminant causes cancer to develop on the molecular level. There is no significant amount in any food for humans in the United States (although there has been contamination of feed for cattle that eventually showed up in small amounts in their milk).

NASH: Diabetes and obesity lead to the development of a condition known as fatty liver and non-alcoholic steatorrheic hepatitis (NASH). This causes the accumulation of fatty acids within the liver cells that eventually cause liver damage. Over a 10-year period, this more than triples the risk of hepatoma and makes it much more likely that cancer will return after surgery.

What most of these processes have in common is that they lead to cirrhosis, which is a severe and irreversible scarring disease of the liver that leads to repeated cycles of cell death and regeneration, eventually allowing some of these cells to become cancerous. In the United States, about one-quarter of people with hepatoma have no risk factors at all, and no reason can be found.

One of the reasons that liver cancer is frequently hard to diagnose is that many of its signs and symptoms are usually vague and nonspecific, meaning that almost any illness can cause them.

• Symptoms such as weakness, fatigue, weight loss, or loss of appetite are common.
• More specific signs of liver damage may appear as the tumor grows, such as an increase in abdominal size due to accumulation of fluid around the liver and intestines (called ascites), jaundice, a yellowing of the skin and eyes along with dark urine.
• Jaundice occurs because of a buildup in the blood of bilirubin, a breakdown product of red blood cells that are usually handled by the liver.
• More severe liver failure may cause internal bleeding and mental changes, including
  • confusion, or
  • uncontrollable sleepiness (encephalopathy) as the liver is no longer able to handle all the harmful chemicals in the blood.
• Rarely, affected people may develop
  • fevers,
  • night sweats, or
  • pain.

Photo of a CT scan showing liver with hepatoma (arrow).

The diagnosis of liver cancer is usually made incidentally, by noticing abnormal blood tests of liver function. Increasingly, people who are known to be at risk (such as people with active hepatitis B or C, or alcoholics with cirrhosis) are being screened by their doctors with periodic blood and imaging tests. Once cancer is suspected, further studies can be done to find out how much of the liver is involved.

The most common radiologic tests used are

• CT scans (computerized tomography, in which X-ray pictures are reassembled into body images),
• ultrasound (using sound waves to create pictures), and
• MRI (magnetic resonance imaging, which uses magnetic fields to get pictures of different body tissues).

Other, more specialized tests are sometimes needed, such as

• an angiogram (taking X-ray pictures of the blood vessels within the liver and the tumor) or
• laparoscopy (inserting a small scope into the abdomen in the operating room to get a closer view of the liver).
• There are also certain tests of proteins made by the tumors that can be measured in the blood, such as AFP (alpha-fetoprotein).

In order to make sure of the diagnosis, it will usually be necessary to biopsy it, that is, to remove a piece of the tumor in order to study it under the microscope and figure out exactly what kind of cancer it is. This is called a biopsy and can be done by pacing a hollow needle into the liver during an ultrasound or CT scanning or during laparoscopy or surgery.

There are many different types of therapy that are used for people with liver cancer. It is very important that the treatment is personalized for each individual since people and tumors may react differently. The main characteristics that help to decide which therapy is best and safest are the functional health of the liver; the size, number, and locations of the tumors; and the person's other medical problems and overall well-being. Because of the complexity of the decisions and the number of treatment options available for many patients, care is frequently coordinated through a multidisciplinary group of physicians specializing in hepatoma.

This team of different specialists usually includes

• surgeons,
• oncologists,
• radiologists,
• gastroenterologists,
• radiation therapists, and
• pathologists.

One of the difficulties in treating liver cancers is that they frequently occur in people with damaged livers. This makes it harder for them to tolerate drugs or procedures that might be needed since side effects may become worse as the liver deteriorates. Therefore, in order to be safe, the options of how best to treat a tumor may be limited if the liver function is poor. Also, since many North-American patients are older and have diabetes, their overall health might prevent the safe application of certain therapies.

Picture of liver transplantation: A new donor liver is placed into a recipient.

The best treatment for primary liver cancer is to remove it surgically. Unfortunately, that is seldom possible; in fact, fewer than 10% of patients are suitable for surgery. This may be because the liver function is too poor due to cirrhosis for the patient to go through surgery safely or because there are several tumors that are too widespread to remove them all. For example, cirrhosis makes it difficult for patients to get safely through almost any type of operation, and when cutting the liver is involved, as many as half might die due to bleeding, infection, or liver failure. Frequently, there are other tiny deposits of cancer elsewhere in the liver that are not visible at the surgery or on scans but will eventually grow back after successful surgery. Despite these issues, however, surgical techniques have steadily improved over the past 20 years, making it even safer and more effective for many people to undergo an operation. Currently, more than half of patients will survive more than five years after the removal of their cancer.

If there is no evidence of the spread of a primary liver cancer beyond the liver, then liver transplantation can be considered. Liver transplantation involves removing the entire liver surgically and replacing it with a healthy liver from a donor. In order for the new liver to be accepted by the body, the immune system has to be severely suppressed and held back from attacking the new liver.

Recent advances in transplant techniques and immune medications have made transplantation the first choice for patients with cirrhosis and small tumors. These are people who would not have been able to have surgery due to their liver disease but now have a greater than 70% chance of living more than five years. Unfortunately, there are not enough donor livers for everyone, and the waiting time on the transplant list can be over a year. The rise in successful experience with live donors and partial-liver transplantation increases the chance that someone can go through with this difficult but potentially life-saving operation.

If surgery is not possible, there are other treatments that can attack the tumor specifically with liver-directed therapy. The tumor may be injected with a toxic material such as pure alcohol or chemotherapy in order to kill it. It can be frozen and killed with supercold liquid nitrogen (cryotherapy). Microwaves, radio waves, or lasers can be directed at the tumor to kill it using heat energy. This is the principle behind radiofrequency ablation, in which a metal probe is inserted into the tumor under ultrasound or CT scan guidance. Thermal (heat) energy is created by radio waves coming from the tip of the probe, and this damages the surrounding cells, killing the tumor. These local techniques are limited to people with only one or two small tumors, in general.

Chemotherapy drugs can be given directly into the blood vessel that feeds the liver and the tumors; in addition, the blood flow to the tumor can be cut off by injecting tiny particles that block the feeding arteries. This procedure, called chemoembolization, attempts to kill the tumor in two ways: by bathing the tumor directly in a very high concentration of chemotherapy and by starving it of its blood supply. Although effective, chemoembolization requires hospital admission and can cause pain, fever, nausea, and liver damage.

A similar technique, using microscopic radioactive particles instead of chemotherapy injected into the blood vessels, is called radioembolization or selective internal radiation therapy (SIRT). This uses radioactive yttrium attached to glass microspheres and may be as effective as chemoembolization for small and multiple tumors.

Radiation therapy uses high-dose energy like X-rays aimed at a small part of the body and can frequently destroy cancer cells. The normal cells of the liver, though, may be more sensitive to radiation than the tumor is, so standard radiation is seldom used. However, there are new specially focused techniques called conformal or stereotactic radiation that may be useful in certain cases.

Chemotherapy refers to drugs that are usually given by pill or by vein. They are designed to work throughout the entire body, not just the liver, so tumors outside the liver will be treated as well. However, chemotherapy does not always work well for primary liver cancers. Since the liver functions by removing poisons from the body, it can treat chemotherapy drugs as just another toxic chemical it needs to resist. Many standard drugs have been tested, and there are certain combinations that can be helpful to shrink cancer. Recently, agents that directly attack the microscopic blood vessels in the tumor, called antiangiogenic drugs, have proven to be very helpful. Sorafenib, the first drug to be approved specifically for hepatoma, was introduced in 2007. Sorafenib is a pill that slows the growth of cancer and helps keep many patients alive longer.

Unfortunately, besides surgery and transplantation, none of the above methods of treatment can be considered to be curative. Although physicians can perform many tests to discover and measure accurately several cancers in the liver, there are almost always more microscopic tumors than can be seen by any technique. Therefore, although local treatments such as radiofrequency ablation, cryoablation, and chemoembolization can kill tumors that are visible, "new" cancers -- ones that are microscopic and invisible at the time of treatment -- will eventually appear. Also, the cirrhosis and conditions that gave rise to the initial cancers will still be there even after successful treatment, so more cancers might actually develop later.

Most of these treatments for liver cancer are still being studied, so some may be offered only in a research study or clinical trial designed to see how well they work. Many liver cancer treatments are investigational or experimental, since there is no one standard approach that can be relied upon to work every time. Researchers continue to look for new drugs and procedures that will be safer, more effective, and can bring a better quality of life to people with any type of liver cancer. For most people, the best treatment will turn out to be a series of different techniques or drugs, finding what helps, and then moving on to the next therapy as it is needed.

It is important to keep in mind that all these techniques are limited by possible side effects, and therefore the decision about how to treat any particular person depends on a very thorough evaluation of the liver function, the state of the blood vessels, how far the tumors have spread, and how healthy the patient has been. Most of all, the patient, family, and physician need to discuss openly what they expect, what may be effective, and what will be safe, and what ultimately makes sense.

In the modern world, unfortunately, another evaluation becomes important in deciding what type of treatment to pursue: the financial one. While many of the techniques described above are effective in some patients, they are not necessarily always covered by insurance plans. Costs of the machines and drugs can be prohibitive to individuals: radioembolization can cost more than $90,000 for a single treatment; sorafenib is more than $5,000 for a month of therapy. This can make individual and institutional decisions even more heart-wrenching than usual on a personal level. At a societal level, these kinds of costs associated with treating this cancer make it even more crucial to find ways to avoid developing it in the first place.

Theoretically, hepatoma should be an almost entirely preventable disease. Hepatitis, alcohol abuse and obesity could all be avoided through social, medical, and lifestyle changes. Some of this has already been attempted around the world, so there is cause for optimism. For instance, children in Taiwan have been immunized against hepatitis B since 1984. This has led, so far, to a 70% decrease in the rate of teenagers developing hepatoma. In the United States, where the incidence is already much lower than it is in Asia, hepatoma due to hepatitis B has fallen by half since immunization began. While there is not yet a vaccine against hepatitis C, this is a much easier virus to avoid now that blood products are being screened and people are more aware of preventing infection from using needles. Once someone is infected, treatment with the drug interferon can reduce the chance of developing hepatoma dramatically. Diabetes and obesity, clearly, can be reduced by modifications in diet and lifestyle, as difficult as that obviously continues to be in our society.

The outcome of hepatoma is extremely variable and depends as much upon the state of the liver and the person's health as on any characteristic of cancer itself.

• Patients with more than a solitary tumor in the setting of cirrhosis might not live for six months,
• while those able to undergo surgery or transplant might be fully cured.
• Therapies such as radiofrequency ablation, chemoembolization, cryoablation, radiosurgery, radioembolization, and systemic therapy are frequently performed sequentially over a patient's lifetime, depending upon the changes as the disease progresses.
• Average survival for patients who are able to be treated with these methods is between one and two years.

Despite these grim statistics, there is still room for optimism in this disease. Creative use of multiple techniques can lead to a significant prolongation of a patient's life while keeping them feeling as well as possible. Experimental drugs are becoming increasingly common as researchers have recognized the molecular defects causing this cancer and used this knowledge to develop new targets. The evolution and improvement in radiologic and interventional technology for treating localized tumors has meant that millions of people who would previously never have been treated have experienced meaningful prolongation of their lives. In fact, the chance of living for more than two years with hepatoma has more than doubled since the early 1990s. Increased medical, scientific, and pharmaceutical attention to this difficult disease will undoubtedly make this even better in the future.