Hepatocellular Carcinoma (HCC)

Risk for Hepatocellular Carcinoma

Most HCC, more than 90%, occurs in people with a chronic liver disease such as viral hepatitis, alcohol-related liver disease, or Nonalcoholic Steatohepatitis (NASH).

The liver has an exceptional capacity to repair itself, also called regenerate, when injured or damaged. While this regenerative capacity usually lasts a lifetime, in cases where there is ongoing chronic injury for an extended period of time, the liver exhausts its capacity to repair itself.

Once the liver reaches this state of repair exhaustion, further damage results in the replacement of the liver hepatocytes with scar tissue, also called fibrosis, rather than normal functioning liver cells. This makes it harder for the liver to perform its normal functions. When the scar tissue eventually replaces large portions of the liver, it is described as cirrhosis of the liver. Cirrhosis is a potentially life threatening condition.

 Some risk factors, like smoking, can be changed while others, like gender, cannot.

• Cirrhosis – is severe scarring of the liver.  Cirrhosis is the result of repeated injury and inflammation and can be caused by several different diseases and conditions.  If the cause of the liver injury is reduced or eliminated, it is possible for the liver to slowly repair itself.

• Race and Ethnicity – in the United States, those most at risk for liver cancer are American Indian & Alaska Natives, Asian and Pacific Islanders, Hispanics and Blacks. 

• Gender – men are at a greater risk than women of developing HCC 

• Age – as people age their risk for cancer increases. Most HCC is diagnosed in people over age 40 and the risk is greater over the age of 65.

• Primary Biliary Cirrhosis (PBC) – is a type of autoimmune disease that can impact the liver and cause cirrhosis.

• Certain inherited liver diseases – people with hereditary hemochromatosis (a condition where the body absorbs too much iron from food) can develop cirrhosis which may lead to HCC. It is important to test family members of patients diagnosed with hereditary hemochromatosis to determine if they are at risk of hemochromatosis and cirrhosis.

• Viral Hepatitis – ongoing infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) can lead to the development of chronic hepatitis and cirrhosis.

• Alcohol and Alcohol Related Cirrhosis – over time, excessive alcohol use can damage and scar the liver leading to cirrhosis 

• Tobacco – smoking increases the risk of liver cancer 

• Nonalcoholic Steatohepatitis (NASH) – this most severe type of nonalcoholic fatty liver disease, common in people with obesity or diabetes. NASH is associated with significant inflammation and can scar the liver and lead to cirrhosis

• Environmental Toxins – exposure to certain toxins, such as dietary aflatoxin from contamination of food by certain molds, increases the risk of liver cancer

• Diabetes – type 2 diabetes (diabetes mellitus) is a risk factor due to its strong association with obesity

• Obesity –  can lead to the build-up of excess fat inside the tissue of your liver and the development of nonalcoholic fatty liver diseases

Diagnosing and Staging Hepatocellular Carcinoma

If liver cancer is suspected, your healthcare team may order certain tests to gather more information. These tests can include: 

• Liver function blood tests – examples include: AST, bilirubin, albumin, prothrombin time, Alkaline phosphatase, ALT, INR, viral hepatitis panel, AFP,

• Imaging tests – examples include: Ultrasound, CT, MRI

• Liver biopsy – is a sample of liver tissue that is removed with a thin needle and looked at under the microscope

Liver biopsy is the gold standard for diagnosing liver cancer, although not needed in all cases since some liver cancers can be diagnosed on imaging. Increasingly, biopsy is being used to help characterize the subtype of liver cancer in order to guide the choice of treatment, especially for advanced liver cancers

If liver cancer is diagnosed, your healthcare team will do additional imaging studies to determine if the cancer has spread from beyond your liver to nearby lymph nodes, the lungs, or other organs in the body. These additional tests allow your healthcare team to stage the liver cancer.

Knowing the stage of the liver cancer allows the treatment team to make recommendations for treatment to ensure the best outcome. There are several different staging systems that are used for staging hepatocellular carcinoma. The two most commonly used systems in the US are the TNM and Barcelona Clinic Liver Cancer systems. 

The TNM System

TNM, which stands for Tumor Node Metastasis is the AJCC (American Joint Committee on Cancer) system for classifying cancer stage and defines the extent of the liver cancer including size, location and number of tumors. TNM Stages are I, II, III, IV.

The Barcelona Clinic Liver Cancer (BCLC) System

is another staging system which includes other aspects including liver function, a person’s overall level of functioning (Performance Status), number and size of tumors. BCLC stages are O, A, B, C, D.

Several other scores are used to assess and determine the health of the liver. The Child-Pugh and MELD scores are frequently used with hepatocellular carcinoma. 

Child-Pugh Score

The Child-Pugh score is a system for assessing the severity of long term liver disease, primarily cirrhosis, including the required strength of treatment and necessity of liver transplant. It provides a forecast of the increasing liver disease severity and expected survival rate. It’s also referred to as the Child-Turcotte-Pugh (CTP) calculator. Child-Pugh scores are Class, A, B, C.

MELD Score

The Model for End-Stage Liver Disease, or MELD score, is used to prioritize adult patients for liver transplants. It determines how soon a person will need a liver transplant. A person must have a MELD score to be put on the United Network for Organ Sharing (UNOS) transplant list. The MELD score is calculated with a mathematical formula using three lab results.

Treatment for Hepatocellular Carcinoma

Hepatocellular carcinoma treatment is guided by several factors including the size of the tumor, number of tumors, location of tumor(s), overall liver function and other health factors. Every person is different and so too is each diagnosis of liver cancer. Working with their treatment team to make a personalized plan based on the cancer stage is important for every patient.

Choosing a doctor and healthcare team is an important and very personal decision. The chosen treatment plan may mean that the doctor that diagnosed the liver cancer is not the one doing the majority of the treatment. Consider working with a multidisciplinary team if possible. A multidisciplinary team is a group of health care professionals from different specialties working together to suggest a treatment and care plan based on your diagnosis, personal health, and preferences. 

Physicians involved in liver cancer care may include

• Hepatologist

• Surgical oncologist

• Medical oncologist

• Radiation oncologist

• Transplant surgeon

• Gastroenterologist

• Interventional radiologist

• Pathologist

• Palliative care physician

Other healthcare professionals involved in liver cancer care

• Oncology nurse

• Oncology social worker

• Physical therapist

• Nutritionist

• Navigator

• Transplant coordinator

• Transplant nurse

• Financial coordinator

• Psychologist

Each treatment is different and most treatments have some side effects that affect people differently. It is important to remember that while people may have some side effects from treatment, most people do not experience all of the potential side effects. Talk often and openly about what to expect for treatment and plan to manage side effects before and when they happen.

Many people do not report side effects from cancer treatment because they fear their treatment team will stop that particular treatment. This is particularly stressful if the treatment is showing success in treating the cancer. Do not hide side effects from the doctor, most side effects can be managed safely and easily so the course of treatment can be maintained.

Treatment Options and Side Effects

Surgery

Surgery is the best option to cure liver cancer because it allows all of the cancer to be removed.

• Resection or Partial Hepatectomy

  • Surgery to remove the part of the liver with cancerous tumor(s)

• Liver Transplant

  • Surgery to remove a person’s liver and replace with a donated liver

 Possible resection side effects

• Pain

• Weakness

• Fatigue

• Temporary liver dysfunction

• Bleeding

• Infection

Possible transplant side effects

• Liver Rejection

• Pain, weakness and fatigue

• Anti-rejection medication side-effects

• Puffiness in the face

• High blood pressure

Ablation

Localized treatment destroys liver tumors without removing them. This is ideal for people with small tumors and when surgery is not a good option.

• Radiofrequency Ablation (RFA)

  • High energy radio waves heat the tumor and destroy the cancer cells with a high frequency current

• Microwave Ablation (MWA)

  • Energy from electromagnetic waves are used to heat and destroy the tumor using a probe

• Cryoablation

  • Extreme cold is used to freeze and destroy cancer cells

• Ethanol (alcohol) Ablation or Percutaneous Ethanol Injection (PEI)

  • Concentrated alcohol is injected directly into the tumor to destroy the cancer cells

 Possible ablation side effects

• Abdominal pain

• Nausea and vomiting

• Diarrhea

• Loss of appetite

Embolization

Embolization is a procedure that injects substances directly into an artery leading to a tumor in the liver. Embolization is most frequently used in people with tumors that are too large to be treated with ablation and who have adequate liver function.

• Trans-arterial embolization (TAE)

  • Particles are injected into the liver to block the blood and nutrient supply to the tumor, thereby starving the cancer cells

• Trans-arterial chemoembolization (TACE)

  • Chemotherapy is injected into the artery and particles are injected to block the artery to keep the chemotherapy close to the tumor 

• Drug-Eluting Bead Chemoembolization (DEB-TACE)

  • Tiny beads filled with chemotherapy are injected into the tumor to kill the cancer cells and particles are injected to block the artery to keep the chemotherapy beads in place

• Radioembolization

  • Also a type of radiation therapy, small beads (called microspheres) that have a radioactive isotope attached to them are injected into the artery where they give off radiation to kill the cancer cells 

Potential embolization side effects

• Abdominal pain

• Nausea and vomiting

• Low grade fever

• Lethargy

• Fatigue

• Ulcers 

Radiation

Radiation therapy uses high energy rays or particles to target and kill cancer cells.

• External Beam Radiation Therapy (EBRT)

  • Radiation from outside the body is directed at liver tumors using x-ray photons and is usually given over multiple days

• Stereotactic Body Radiation Therapy (SBRT)

  • High doses of radiation are directed at the liver tumors, this treatment is similar to EBRT but the total dose is given in a shorter amount of time.

• Radioembolization

  • Small beads (called microspheres) that have a radioactive isotope attached to them are injected into the artery where they give off radiation to kill the cancer cells 

• Proton Beam Radiation Therapy

  • Protons, rather than photons, are used as the energy source to target and kill cancer cells

  • Proton therapy has the advantage of very precise application of radiation to the treatment zone

  Potential radiation therapy side effects

• Skin changes in radiated areas, ranging from redness to blistering and peeling

• Nausea and vomiting

• Fatigue

• Diarrhea

• Loss of appetite

Systemic Therapy 

Systemic therapy is given to treat advanced liver cancer that has spread throughout the liver and to other parts of the body. Treatment is given by pills (oral therapy) or injected directly into the bloodstream.

Targeted drug therapy

Kinase inhibitors – kinase inhibition can be accomplished using chemical pills or monoclonal antibodies

• Kinases are proteins that carry important signals to the cell’s control center and help cancer grow. Kinase inhibitor drugs block several of these proteins from working which can stop cancer growth

• Kinase inhibitors are pills

• Examples of kinase inhibitors are:

  • Sorafenib (Nexavar)

  • Lenvatinib (Lenvima)

  • Regorafenib (Stivarga)

  • Cabozantinib (Cabometyx)

Potential kinase inhibitor side effects

• Fatigue

• Loss of appetite

• Hand-foot syndrome (redness and irritation of the hands and feet)

• High blood pressure

• Weight loss

• Diarrhea

• Abdominal pain 

Monoclonal Antibodies

• Monoclonal antibodies are lab made versions of antibodies (immune system proteins) that attach to a certain target to stop the tumor from making new blood vessels. By stopping new blood vessel growth the cancer cells are starved and die.

• The drugs are infused into a vein in a hospital or doctor’s office over a period of time

• Examples of monoclonal antibodies are:

  • Bevacizumab (Avastin) – which targets VEGF - is given in combination with Atezolizumab (Tecentriq)

  • Ramucirumab (Cyramza) – which targets VEGFR2

Potential monoclonal antibody treatment side effects 

• High blood pressure

• Tiredness (fatigue)

• Bleeding

• Low white blood cell counts (with increased risk of infections)

• Headaches

• Mouth sores

• Loss of appetite

• Diarrhea

• Increased encephalopathy (Ramucirumab)

Immunotherapy – Immune Checkpoint Inhibiting Monoclonal Antibodies

The use of medicines to help a person’s own immune system find and destroy cancer cells. Immune checkpoint inhibitors uses proteins on immune cells that need to be turned on or off to start an immune response. These drugs are infused into a vein in a hospital or doctor’s office over a period of time.

• PD-1 and PD-L1 Inhibitors

  • PD-1 and PD-L1 work together to boost an immune response against cancer cells

  • Examples of PD-1 and PD-L1 inhibitors are:

    • Atezolizumab (Tencentriq) is given in combination with Bevacizumab (Avastin) 

    • Pembrolizumab (Keytruda)

    • Nivolumab (Opdivo)

• CTLA-4 Inhibitors

  • CTLA-4 inhibitors boost the immune response 

  • Example of a CTLA-4 Inhibitor

    • Ipilumamab (Yervoy)

Potential monoclonal antibody treatment side effects 

• Feeling tired or weak

• Fever

• Cough

• Nausea

• Itching

• Skin rash

• Loss of appetite

• Muscle or joint pain

• Constipation or diarrhea

• Immune mediated events – where the body attacks other organs in the body because of immunotherapy treatment 

Supportive (Palliative) Care

Palliative care is supportive care that aims to help a person maintain a high quality of life by managing the symptoms of cancer rather than cure the cancer.

There are many specialties that make up a palliative care team. These may include medical professionals that provide physical, emotional, cultural, spiritual and social support to meet a person’s unique needs. They also provide support to families and caregivers.

Many people believe that palliative care is hospice. The two are similar because their goal is to provide comfort and care to people living with an illness. Palliative care can be given at any age and at any stage of illness.  Hospice is medical care to help someone with a terminal illness live well for as long as possible.

Clinical Trials

Clinical trials are research studies that involve people. Through clinical trials, new treatments and ways to improve liver cancer care are moved forward. Clinical trials also determine if treatments are safe and effective in the treatment of liver cancer.

 Clinical trials evaluate:

• New diagnostic methods

• New drugs and medicines

• New combinations of treatments

• New approaches to surgery or radiation

Clinical trials are highly controlled and regulated. They can be sponsored by the federal government, medical institutions, pharmaceutical companies, and private foundations.

Survivorship in Liver Cancer

Once treatment is completed ask about a treatment summary as a way to record the exact diagnosis, anti-cancer treatments and other procedures and tests that were a part of the liver cancer journey. This can become a helpful tool for any doctors that provide care in the future.

Your journey is uniquely yours and liver cancer can be a difficult disease to treat. Consider seeking support to help you and your loved ones navigate the challenges.