Advanced Hepatocellular Cancer - Causes, Symptoms, Diagnosis, and Treatment

Introduction:

Several types of cancer can occur in the liver. Among the most common is hepatocellular carcinoma, which arises from the liver cells or hepatocytes. Most liver cancers occur due to the spread of the tumor from other organs, but hepatocellular cancer occurs directly from the liver cells. So it is called primary cancer of the liver.

What Is Hepatocellular Cancer?

Hepatocellular carcinoma (HCC) is cancer arising in the liver cells. It is called a primary tumor arising in the liver. It is most commonly seen in people with chronic liver diseases like liver cirrhosis or non-alcohol-related fatty liver diseases. It is commonly seen in the male population above the age of 60 years. It is a slow-growing tumor initially, but as cancer progresses, the speed of growth will also increase.

What Are the Causes of Hepatocellular Carcinoma?

Liver cancer occurs when there is a change in the DNA (deoxyribose nucleic acid). A known factor like cirrhosis of the liver causes most liver cancers. Still, sometimes it is seen in people with no underlying diseased condition, and the cause of liver carcinoma is unclear. The conditions that will increase the chance of getting hepatocellular cancer include:

• Hepatitis B caused by the hepatitis B virus, which is transferred from person to person by blood, sexual contact, other body fluids, or from mother to child. It can be prevented by vaccination.

• Hepatitis C (caused by the hepatitis C virus, transferred through blood transfusion from affected patients).

• Liver cirrhosis (when the cells in the liver are destroyed and replaced with scar tissues).

• Type 2 diabetes mellitus.

• Excess alcohol consumption.

• Smoking.

• Obesity can lead to non-alcoholic fatty liver disease, leading to liver cancer.

• Long-term use of anabolic steroids (to increase the body's muscle mass, testosterone- male sex hormone are used sometimes by athletes).

• The storage of too much iron in the liver and other organs is called iron storage disease. These people can develop liver cancer.

• Aflatoxin (a poisonous carcinogen produced by certain molds) is associated with a high risk of liver cancer.

What Are the Symptoms of Hepatocellular Carcinoma?

There are few signs and symptoms during the early stages of hepatocellular cancer. But as cancer progresses, the signs and symptoms can appear. The symptoms can include:

• Loss of weight without diet control or exercise.

• Loss of appetite.

• Nausea and vomiting.

• Pain in the upper abdominal region.

• General weakness and fatigue.

• Swelling or bloating in the abdominal region.

• Jaundice (yellow discoloration of the skin and the sclera of the eyes).

• White and chalky stools and dark urine.

• Fever.

• Persistent itching of the skin.

• Blood in stools (gastrointestinal hemorrhage).

What Are the Risk Factors of Hepatocellular Cancer?

The factors that increase the risk of hepatocellular cancer include:

• Chronic liver infections with hepatitis B or hepatitis C virus.

• Liver cirrhosis.

• Inherited liver diseases.

• Non-alcoholic fatty liver diseases.

• When exposed to aflatoxins.

• Diabetes.

• Chronic alcohol drinking.

How Is Hepatocellular Cancer Classified?

According to the Barcelona Clinic liver cancer (BCLC) staging system, hepatocellular cancer can be classified as follows:

• Very Early Stage: The tumor size is less than 2 centimeters. The portal vein has no increased pressure (the portal vein is the main blood vessel of the liver). Bilirubin levels are normal (bilirubin causes jaundice). Surgery is usually recommended at this stage.

• Early Stage: The tumor size is less than 5 centimeters. In this stage, there can be various changes in portal vein pressure and bilirubin levels, like there can be no portal hypertension and normal bilirubin, or there can be portal hypertension and normal bilirubin or portal hypertension and increased levels of bilirubin. These people may be ideal for a liver transplant, surgery, or radiofrequency ablation (RFA).

• Intermediate Stage: The tumor may be large, multinodular, with a size of more than 5 centimeters. The tumor may spread to blood vessels, lymph nodes, or other organs. Regional therapies are preferred, like transarterial chemoembolization.

• Advanced Stage: The tumor invades the portal vein, and cancer will spread to other parts of the body, such as the lungs, bones, and lymph nodes. Targeted therapy is recommended for these patients.

How to Diagnose Hepatocellular Cancer?

Diagnosis of liver cancer starts with a physical examination describing the symptoms and medical history. Other diagnostic procedures are:

• Blood Test: To measure liver function.

• Alpha-Fetoprotein (AFP) Testing: AFP is a protein seen in unborn babies. The level of AFP is high in the fetus and gradually decreases as age increases. The AFP level is high in hepatocellular cancer cases. So alpha-fetoproteinis considered a tumor marker in hepatocellular carcinomas.

• Imaging Tests: Ultrasound (uses sound waves to create images), MRI (magnetic resonance imaging) uses strong magnetic fields and radio waves to produce a detailed view of the liver, CT (computed tomography) uses a combination of x-rays and computer technology to produce cross-sectional slices of the liver, angiography (to visualize inside the blood vessels and organs).

• Liver Biopsy: A sample of liver tissue is taken and examined under a microscope.

What Are the Treatments for Hepatocellular Cancer?

The treatment for hepatocellular cancer depends on the tumor's size and location, the liver's functioning ability, and overall health. The treatment includes

• Surgery: A portion of the liver and normal cells surrounding the tumor is surgically removed. This is called partial hepatectomy.

• Liver Transplant Surgery: If the liver is not functioning properly, replace it with a healthy liver from a deceased donor.

• Destroying the Cancer Cells With Heat or Cold: Killing the cancer cells using extreme heat and cold is called an ablation procedure. This procedure is recommended for people who cannot undergo surgical treatment. There are different types of ablation procedures, such as cryoablation, radiofrequency ablation, and microwaves.

• Radiation Therapy: Stereotactic body radiotherapy (SBRT) focuses many radiation beams on one body part.

• Chemoembolization or Radioembolization: Delivering chemotherapeutic drugs and drugs directly to the cancer cells through a catheter passed through a blood vessel.

• Targeted Drug Therapy: Attack specific areas in cancer cells in advanced liver cancers.

• Immunotherapy: The body’s immune system is used to fight against cancer cells. Also an option in case of advanced hepatic cancer.

• Clinical Trials: New cancer treatments are performed.

What Are the Treatments for Advanced Hepatocellular Cancer?

First-Line Systemic Therapy

1. Atezolizumab + Bevacizumab Combination Therapy: This multi-agent combination therapy is the first-line treatment for advanced hepatocellular carcinoma. Atezolizumab and Bevacizumab are monoclonal antibodies. They inhibit both T-cell apoptosis and angiogenesis. The combination of these medications improves survival rates compared with the treatment of Sorafenib. Adverse effects include hypertension and proteinuria.

2. Sorafenib: It is a tyrosine-protein kinase inhibitor. Sorafenib is used when Atezolizumb and Bevacizumab combination therapy is contraindicated. Side effects include diarrhea, hand and feet skin irritation, electrolyte derangements, and weight loss.

3. Lenvatinib: It is also a tyrosine-protein kinase inhibitor that targets multiple pathways within angiogenesis. A clinical trial showed Lenvatinib is non-inferior to Sorafenib. In the same trial, patients who were treated with Lenvatinib had hypertension, loss of appetite, and weight loss, while those treated with Sorafenib had hand-foot skin reactions and diarrhea.

Second Line Systemic Therapy

1. Cabozantinib: It is a tyrosine-protein kinase inhibitor targeting mesenchymal-epithelial transition that disrupts the hepatocyte growth factor pathway, which is important for hepatocellular cancer oncogenesis. Adverse effects like diarrhea, hypertension, loss of appetite, and nausea are seen.

2. Regorafenib: It is also a tyrosine kinase inhibitor. Side effects are similar to Cabozantinib, with an increased chance of diarrhea.

3. Apatinib: Used in patients with a previous history of hepatitis B. Adverse effects include hypertension and thrombocytopenia.

4. Nivolumab: It is an immunoglobulin G antibody that targets programmed cell death to improve the antitumor properties of T cells. There are only a few side effects associated with this drug.

5. Pembrolizumab: It is a monoclonal antibody used in advanced hepatocellular cancer.

6. Ramucirumab: Monoclonal antibody which is directed against vascular endothelial growth factor. The side effect of this drug is mild, with only hypertension and proteinuria.

7. Ipilimumab: Monoclonal antibody targeting cytotoxic T lymphocytes.

Locoregional Therapy

A procedure that blocks blood vessels using tiny gelatin beads is called embolization. This method is used to treat people with advanced hepatocellular cancer. But this method is contraindicated in patients having vascular diseases.

1. TACE: Transarterial chemoembolization or TACE is done in patients with tumor invasion on a portal vein branch. This method injects a chemotherapeutic agent into the hepatic artery, which flows toward the tumor, followed by embolization.

2. Y-90 Trans Arterial Radio Embolization: In this method, isotope yttrium 90 is transferred in small quantities to malignant areas through branches of the hepatic artery.

3. Hepatic Artery Infusion Chemotherapy: Direct delivery of high concentration of chemotherapeutic agents.

Surgery

Surgical methods include hepatectomy or en bloc resection. Hepatectomy is the surgical removal of the liver. It can be partial hepatic resection when only a part of the liver is removed.

What Are the Preventive Measures for Hepatocellular Cancer?

• Reduce alcohol consumption.

• Vaccination for hepatitis B.

• Usage of a clean needle for injections.

• Avoid contaminated blood transfusions.

Conclusion:

Hepatocellular cancer is the most common cause of death in patients with liver cirrhosis. If diagnosed early, hepatocellular cancer treatment will have a good prognosis and can be cured. In advanced cases, the complete cure of the cancer is not possible, but treatment and support can be given to patients to live longer and better.