Stage 4 Liver Cancer: What to Expect

Stage 4 liver cancer is the most advanced form of the disease. In stage 4 liver cancer, a tumor has begun in the liver and spread to either nearby lymph nodes and/or distant lymph nodes and organs.

With more than 42,000 cases being diagnosed each year, liver and intrahepatic bile duct cancer will be diagnosed in approximately 1% of people in the United States over the course of their lifetime. That said, compared to other forms of cancer, liver cancer is relatively rare.

It is more common in men than it is in women, and especially in men of Black, Native American, Hispanic, and Asian or Pacific Islander descent.

Liver cancer is also sometimes called hepatoma or hepatocellular carcinoma (HCC).

What It Means When Liver Cancer Is Stage 4

Stage 4 liver cancer is diagnosed when the disease has spread beyond the liver and into other organs and/or lymph nodes. It may be further broken down into other categories that are designated by letters and numbers, which are defined by the American Joint Committee on Cancer.

Liver cancer staging can be quite complex, but staging can help determine how far cancer has spread beyond the liver and what treatments might be used. The substages of liver cancer are based on tumor size (T), involvement of lymph nodes (N), and spread to other parts of the body (M).

Factors that are used to stage liver cancer include:

• T stands for tumor size, tumor number, and if the tumor has spread to nearby structures.
• N stands for lymph nodes and if the tumor has spread to any that are near the liver.
• M stands for metastasis—that is, if the tumor has spread beyond the liver to lymph nodes that are further away and if it has spread to other organs (such as the lungs).

Stage 4 Grouping

Further staging, called stage grouping, uses numbers to indicate how many tumors, lymph nodes, or other organs are involved. This number is applied to each of the T, N, and M designations. For tumors, the number used corresponds to the number of tumors present (T1 would mean one tumor).

For N and M, a "0" would indicate that spread beyond the liver is not present, while a "1" or higher would mean that one or more lymph nodes or other organs are involved (N1 would mean one or more lymph nodes, and M1 would mean spread beyond the liver). 

Based on these numbers, stage 4 liver cancer would be classified as one of two types:

• Stage 4A: Tumor that has spread to the lymph nodes but not distant organs
• Stage 4B: Tumor that may or may not have spread to the lymph nodes and has spread to distant organs

There are other systems in place to stage liver cancer, so it is important to have a physician explain which staging system is being used and the meaning of the stage.

Also, there may be cancers that don't fall squarely into one of the predefined stages. For instance, in some cases, the number of tumors can't be defined or isn't available, in which case "TX" would be used.

Stage 4 Liver Cancer Symptoms

In the first stages of liver cancer, there may not be any symptoms. Further, liver cancer signs and symptoms aren't always directly related to the stage of the cancer. How the disease affects each person is highly individualized.

Some of the signs and symptoms of advanced liver disease, which increases the risk of liver cancer, can include:

• Abdominal pain
• Abdominal swelling and fluid in the abdomen (ascites)
• Appetite loss
• Feeling full after eating only a little (early satiety)
• Generalized itching
• Jaundice (yellowing of the skin and the whites of the eyes)
• Liver enlargement
• Nausea and/or vomiting
• Pain in the right shoulder blade
• Spleen enlargement
• Unintended weight loss
• Swelling in the legs

In some cases, a liver cancer tumor may start to produce hormones. Those hormones may cause signs and symptoms that are outside of the liver and affect other organs and systems in the body. These can include:

• Gynecomastia (male breast enlargement) or testicle shrinkage
• Erythrocytosis: High levels of red blood cells
• High cholesterol
• Hypercalcemia: Increased calcium, which may lead to feeling confused, nauseous, or weak, or cause constipation or muscle problems
• Hypoglycemia: Lowered blood sugar levels, which may cause fatigue or fainting

Causes

Several risk factors may contribute to the development of liver cancer. Risk factors are conditions, behaviors, or other factors that make a person more susceptible to developing a liver disease.

It's estimated that 40% of liver cancer is associated with hepatitis B, 40% with hepatitis C, 11% with alcohol consumption, and 10% from other causes.

Cirrhosis

Damage in the liver can lead to scarring; the most advanced stage of scarring is called cirrhosis.

In addition to alcohol abuse, infection with hepatitis B or C, nonalcoholic fatty liver disease, hereditary liver diseases, autoimmune hepatitis, chronic heart failure, long-term use of some types of medications, and liver diseases such as primary biliary cholangitis and primary sclerosing cholangitis are some of the reasons that scarring may occur.

Cirrhosis is progressive (becomes more serious with time) and it develops over a period of years. It's important to remember that while cirrhosis is a risk factor for liver cancer, not everyone with cirrhosis will develop cancer.

Hepatitis B and C

Long-term infection with the hepatitis B virus is a risk factor for liver cancer. The risk of developing liver cancer may be up to 12 times higher in people with hepatitis B.

The risk of liver cancer may be nine times higher in people with chronic infection with hepatitis C.

Nonalcoholic Fatty Liver Disease (NAFLD)

NAFLD tends to occur more frequently in people who have a body mass index (BMI) over 30, have type 2 diabetes, have higher fat content in their blood, or have metabolic syndrome. NAFLD may affect up to 25% of adults.

Related Conditions

Several other conditions that affect the bile ducts and the liver may also carry a risk of developing liver cancer. These include Wilson disease, alpha-1 antitrypsin deficiency, hemochromatosis, glycogen storage disease, primary biliary cholangitis, and primary sclerosing cholangitis, autoimmune hepatitis. 

Aflatoxins

Aflatoxins are a poisonous, carcinogenic (causes cancer) mycotoxin. They are produced by fungi that grow on certain types of crops, including maize, peanuts, cottonseed, and tree nuts.

Exposure to aflatoxins is more common in parts of the developing world where these crops are staple foods and where there is less ability to store foods without the risk of contamination. Aflatoxins are a cause of liver cancer in some developing areas of the world.

Anabolic Steroid-Induced Liver Injury

The use of anabolic steroids classed as "appearance and performance-enhancing drugs" is seen in both amateur and professional athletes, even though they are prohibited in many sports and are only legally available by prescription.

Anabolic steroids are known to cause liver injury. They have rarely been associated with a more rare type of liver cancer called angiosarcoma.

It's important to make athletes, coaches, and physicians aware of the possibility of irreversible liver damage.

Diagnosis

A diagnosis of liver cancer is made after performing a battery of tests. Sometimes the suspicion of liver cancer may be raised by an abnormal ultrasound. Ultrasound uses sound waves to create an image of the organs inside the body.

For confirmation, other tests are needed. Multiphasic computerized tomography (CT) or magnetic resonance imaging (MRI) with contrast is recommended to confirm the diagnosis and stage.

Computerized tomography is a series of X-rays used to create a cross-sectional image of the abdomen. Magnetic resonance imaging creates images of the structures in the abdomen using powerful magnets and radio waves.

Blood tests will include liver function tests to determine how well the liver is working and screening for alpha-fetoprotein, a tumor marker frequently associated with liver cancer. A liver biopsy may be done, in which a piece of liver tissue is removed to examine for evidence of disease.

Stage 4 Liver Cancer Treatment

Stage 4 liver cancer is not curable. However, treatment can help manage its symptoms and progression.

The treatment for stage 4 liver cancer will depend greatly upon the stage of cancer and how well the person who has cancer is otherwise.

Liver cancer might be grouped into one of three categories, which will dictate possible treatment options:

• Potentially resectable or transplantable
• Inoperable cancer that has not spread beyond the liver
• Advanced cancer

Medications

Stage 4 liver cancer is the advanced form, and therefore only certain treatments might be offered. For instance, a liver transplant is generally not an option for stage 4. Surgery to remove parts of the liver (such as a partial hepatectomy or segmentectomy) will also likely not be an option for stage 4 disease.

In most cases, the therapy offered will include medications, plus treatments that help with symptoms and/or pain.

One type of therapy for stage 4 liver cancer is using medications that activate the patient's immune system. This is called immunotherapy. The first line of therapy for stage 4 liver cancer might include Tecentriq (atezolizumab) and Avastin (bevacizumab).

Tecentriq is a drug that can increase the ability of the body's own immune system to target the cancer. It might be used along with another drug, Avastin, which is a monoclonal antibody. These medications are given by infusion (intravenously) on a schedule that can be anywhere from two to four weeks.

If the first choice of medications isn't working or isn't an option, several other drugs might be used. In some cases, these drugs might only be used after one or more drugs have already been tried and have proven not helpful:

• Nexavar (sorafenib) and Lenvima (lenvatinib) are kinase inhibitor targeted drugs and can be used in first line treatment of liver cancer. Stivarga (regorafenib) and Cabometyx (cabozantinib) are two other targeted drugs that are also kinase inhibitors and can be used in second line treatment of liver cancer. All these drugs are given orally.
• Cyramza (ramucirumab) is a monoclonal antibody classified as targeted therapy and given by infusion, usually every two weeks.
• Keytruda (pembrolizumab) and Opdivo (nivolumab) are two other forms of immunotherapy given by infusion in intervals between two and six weeks.
• Yervoy (ipilimumab) is a type of immunotherapy given along with Opdivo and is only used after other cancer treatment medications have not worked. It is given by infusion every three or four weeks.

Other medications may be given for stage 4 liver cancer if the first-line therapies have not worked to address the cancer.

Radiation Therapy

The use of high-energy particles is another potential treatment for stage 4 liver cancer. Two types that might be used are external beam radiation therapy (EBRT) and stereotactic body radiation therapy (SBRT).

EBRT is similar to an X-ray. The treatment lasts a few minutes, but it may need to be repeated daily over a series of weeks. SBRT is a treatment technique that has been developed more recently and may help preserve healthy liver tissue.

Clinical Trials

Clinical trials for new treatments, which might be medications but could also include radiation therapy or new ways to deliver approved medications, might also be an option for stage 4 liver cancer. Patients will want to ask their physicians about the availability of clinical trials and the potential to get involved in one.

Life Expectancy

The benchmark for the prognosis in cancer is usually the five-year survival rate. This is the number of patients that have survived five years after a diagnosis. It differs based on the stage of the cancer.

Data on stage 4 liver cancer life expectancy comes from the Surveillance, Epidemiology, and End Results (SEER) program, part of the National Cancer Institute. SEER doesn't use cancer stages 1 through 4, but instead classifies cancers into localized, regional, and distant. Stage 4 liver cancer falls under the distant group.

Statistics can be helpful, but they must also be put into perspective. Not every possibility is taken into account for five-year survival rates, so each patient should work with a healthcare team to understand their individual prognosis.

Also, scientists, researchers, and physicians are always learning new things about treating liver cancer. It's important to keep in mind that statistics are, by their nature, based on historical data.

Coping

A diagnosis of stage 4 cancer will bring up many complicated emotions. Further, it will affect family, friends, and coworkers, and it's not always possible to predict what that will look like. Therefore, it's important to put a support structure and a toolkit in place to help cope with all these issues.

One of the first steps is often in education. Providers and advocacy groups for liver cancer are the most important information sources on the next steps, including treatment and emotional wellness.

With a challenging prognosis, there will be a need for support for the patient and their caregivers and loved ones. A space for everyone's emotional well-being should be part of an overall holistic treatment plan.

Engaging with a mental health professional and others such as social workers and patient advocacy groups can help address the emotional needs of patients and their families.

In particular, patient advocacy groups can help with everything from finding a doctor for a second opinion to in-person or online support groups for patients, families, and caregivers to finding out more about treatment options.

Some people may also find support from their faith leaders or other groups in their community who are trusted sources of information and connection.