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Hepatocellular Carcinoma

Updated : May 13, 2024





Background

Hepatocellular carcinoma is a primary tumor of the liver that accounts for more than ninety percent of primary liver tumors. It is present in roughly 85% of patients diagnosed with liver cirrhosis, hepatocellular carcinoma.

Hepatocellular Carcinoma is currently the fifth leading cause of cancer throughout the world. It is also the second most common cause of cancer death among males following lung cancer. HCC has a five-year survival rate of 18 percent, second only to pancreatic cancer.

Risk factors for Hepatoceullar Carcinoma are:

  • Hepatitis B and C
  • Non-alcoholic fatty liver disease
  • Alcoholic liver disease

80-90% of cirrhotic patients develop Hepatocellular Carcinoma. 2-4% of people with cirrhosis develop HCC each year.

Epidemiology

Hepatocellular carcinoma (HCC) is currently the fifth most prevalent cause of cancer globally.   In 2018, almost 841,000 new cases of HCC were identified. In 2018, 780,000 deaths were attributed to HCC.

HCC is three times more prevalent in men than in women.  More than 80 percent of new instances of HCC occur in developing nations with high rates of hepatitis B infection, such as Sub-Saharan Africa, South-East Asia, and China. Non-Alcoholic Fatty Liver Disease is now the major cause of HCC in the globe, particularly in western nations.

Between 2016 and 2030, the incidence of HCC is projected to increase by 122 percent in the US due to the increasing incidence of obesity and diabetes. The median age of Hepatocellular Carcinoma patients in the United States is 64 years. Currently, the majority of people who have been diagnosed with HCV infections were born between 1945 – 1965.

Anatomy

Pathophysiology

Cirrhosis is a crucial phase in the viral carcinogenesis of hepatocellular cancer. HBV oncogenesis is primarily caused by the integration of the hepatitis B viral genome into the host genome. The insertion of viral DNA into telomerase reverse transcriptase (TERT) promoter regions in the human genome, resulting in mutation, is responsible for 60% of all instances of head and neck cancer.

Other genetic changes include mutations in TP53 (affecting the cell cycle), beta-1 catenin (CTNNBI), axis inhibitor-1 (AXINI), AT-rich interaction domain-containing protein 1A (ARID1A), and ARID2 (chromatin proliferation).

Chronic hepatitis C virus infection, followed by fibrosis, necrosis, and regeneration, contributes to the development of HCC. In liver carcinogenesis, viral structural and non-structural proteins such as NS3, NS4A, NS4B, NS5A, and NS5B serve as molecular markers. Most patients diagnosed with cirrhosis or in advanced stages of fibrosis have a high occurrence of HCV-associated HCC.

Etiology

The etiological factors responsible for the development of hepatocellular carcinoma include:

  • Hepatitis B and C
  • Non-Alcoholic liver Steatohepatitis and Non-Alcoholic Fatty Liver Disease
  • Alcoholic liver diseases
  • Aflatoxins
  • Glycogen Storage Disease
  • Alagille Syndrome
  • Acute Intermittent Porphyrias
  • Iron Overload
  • Wilson Disease
  • Alpha one Antitrypsin Disease
  • Hypercitrullinemia

Viral Hepatitis:

The chronic hepatitis B virus and the chronic hepatitis C virus are connected with almost 70% of hepatocellular cancer cases. Hepatitis B virus (HBV) is an enclosed, partially double-stranded, circular DNA virus that is a member of the Hepadnavirus family. Hepatitis B is the most prevalent cause of chronic hepatitis on a global scale, currently affecting over 250 million people.

HBV oncogenesis is primarily caused by the merging of the hepatitis B viral genome into the host genome. The insertion of viral DNA into telomerase reverse transcriptase (TERT) promoter regions in the human genome, resulting in mutation, is responsible for 60% of all instances of head and neck cancer.

Other genetic changes include mutations in TP53 (affecting the cell cycle), beta-1 catenin (CTNNBI), axis inhibitor-1 (AXINI), AT-rich interaction domain-containing protein 1A (ARID1A), and ARID2 (chromatin proliferation).

Hepatitis B and Hepatitis C virus infections account for 56 percent and 20 percent, respectively, of HCC cases diagnosed worldwide. Hepatocellular carcinoma can develop in the absence of cirrhosis in individuals infected with hepatitis B. Over 80% of HBV-related HCCs are accompanied with cirrhosis.

Elevated blood HBV DNA levels (equivalent to or greater than 10,000 copies/mL) are a significant risk factor for hepatocellular carcinoma in HBV-positive patients. This is independent of the patient’s hepatitis B e antigen status. Additionally, the presence of hepatitis B e antigen is linked with a higher prevalence of HCC.

This could indicate an extended replication process. HBV genotype C is linked to an increased risk of HCC. Patients with a low hepatitis B viral load but elevated levels of hepatitis B surface antigen with concentrations over 1000 IU/mL are strongly related with HCC. HCC is more likely to develop when an individual is infected with both the hepatitis C virus and the hepatitis delta virus.

Hepatitis C virus (HCV) is a plus-sense, partly double-stranded RNA virus comprising 11 primary genotypes and 15 subtypes. HCC is usually related with HCV genotype 1b.   HCV does not assimilate into the genome of the host. Cirrhosis is an important phase in the viral carcinogenesis of Hepatocellular Carcinoma.

Chronic hepatitis C virus infection, followed by fibrosis, necrosis, and regeneration, contributes to the development of HCC. In liver carcinogenesis, viral structural and non-structural proteins such as NS3, NS4A, NS4B, NS5A, and NS5B serve as molecular markers.

The majority of patients with cirrhosis or advanced stages of fibrosis develop HCV-associated HCC. In patients without cirrhosis, fewer instances of HCV-related HCC have been recorded.  20% of all HCC cases identified globally are caused by Hepatitis C. There is a greater risk of incidence if an individual is also infected with Hepatitis B.

Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Liver Steatohepatitis

Non-alcoholic fatty liver disease is characterized by an excess amount of fat in the hepatocytes, without the presence of alcohol consumption. NAFLD is typically associated with metabolic syndrome. Conditions such as insulin resistance, hypertension, hypertriglyceridemia, and abdominal obesity are associated with the metabolic syndrome, which raises cardiovascular risk.

NAFLD is now the major cause of HCC in the globe, particularly in western nations. 13% of individuals diagnosed with HCC without cirrhosis were also diagnosed with NAFLD.

Alcohol and Alcoholic Liver Diseases

In the United States, 30% of head and neck cancers are linked to a background of excessive alcohol consumption. Alcohol can cause HCC both directly and indirectly. Through cirrhosis, alcohol can indirectly induce liver cancer. Increased alcohol consumption increases oxidative stress and inflammation. Consuming more than 80 g of alcohol each day multiplies the risk of HCC by five.

Aflatoxins

Mycotoxin Aflatoxin B1 is generated by the fungi Aspergillus flavus and Aspergillus parasiticus. These fungi are prevalent in Sub-Saharan Africa and Southeast Asia, where they contaminate grains. The primary cause of carcinogenesis seems to be mutations in tumor suppressor genes (p53). Aflatoxin B1 is connected with an increased incidence of HCC in patients suffering with chronic Hepatitis B.

Genetics

Prognostic Factors

There are over 6 accepted staging systems used to determine the survival rates for Hepatocellular Carcinoma.

All of these systems take into account the following 4 prognostic factors:

  • Size and quantity of tumor
  • The extent of spread of the tumor
  • Presence of metastases
  • Severity of accompanying liver disease

It is challenging to successfully stage individuals with hepatocellular carcinoma due to the numerous variables. Therefore, there is no optimal system that is ideal for predicting survival rates.

As a rule of thumb, treatment for each should be personalized patient and not based on an algorithmic approach, since aggressive treatments are generally effective for certain patients with HCC. A multidisciplinary approach is suggested for achieving better outcomes.

Clinical History

Physical Examination

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Medication

 

regorafenib

40

mg

Tablet

Oral

4 times a day

The medication is continued until the disease is reduced to acceptable toxicity



Dose Adjustments

In case of adverse reactions, the dose is modified or reduced First dose reduction: 120 mg total daily Second dose reduction: 80 mg daily In case the patient is unable to tolerate 80 mg daily, discontinue the treatment

sorafenib

400

mg

Tablet

Oral

every 12 hrs

In case of toxicity of the skin, reduce or discontinue the dose



doxorubicin

CTACE intra-arterial:

50 - 75

mg/m^2

Intravenous (IV)

as a single dose via intra-arterial injection every 2 months for a maximum of 3 doses.
DEB-TACE intra-arterial: 150 mg administered via loaded drug-eluting bead every 2 months for a maximum of 3 doses.



ramucirumab (Rx)

8

mg/kg

Solution

Intravenous (IV)

every 2 weeks

1

hr



cabozantinib

60

mg

orally

once a day

The treatment needs to be continued until disease progression or unacceptable toxicity occurs



atezolizumab

1200

mg

Intravenous (IV)

over 1 hr

and followed by 15 mg per kg of bevacizumab on the same day for every three weeks
Continue the course until disease progression, or unacceptable toxicity occurs
if bevacizumab is discontinued for toxicity, the dosage recommended for atezolizumab is:
840 mg given IV every two weeks or 1200 mg given IV every three weeks, or 1680 mg given IV every four weeks
Continue the course until disease progression, or unacceptable toxicity occurs
Note:
the first infusion administered for over 60 minutes if well-tolerated, and subsequent infusions administered for around 30 minutes



ipilimumab

ipilimumab 3 mg per kg given IV over 30 minutes every 3 weeks with nivolumab 1mg per kg given IV over 30 minutes on the same day for 4 doses
After completing four doses of combination, nivolumab is given as a single agent.
Continue the therapy until disease progression or unacceptable toxicity occurs.



lenvatinib 

For <60 kg: 8 mg orally each day
For ≥60 kg: 12 mg orally each day



regorafenib 

regorafenib is indicated in the treatment of hepatocellular carcinoma in patients who have undergone previous treatment with sorafenib
A dose of 40 mg is administered four times daily for initial 21 days of every 28-day cycle
The medication is continued until the disease is reduced to acceptable toxicity



Dose Adjustments

In case of adverse reactions, the dose is modified or reduced
The pattern of dose reduction goes like this
First dose reduction: 120 mg total daily
Second dose reduction: 80 mg daily
In case the patient is unable to tolerate 80 mg daily, discontinue the treatment

bai ji 

6 - 15

g

Orally 

day



ethiodized oil 

Slowly inject 1.5 to 15 mL under continuous radiologic monitoring.
The total dosage should not exceed be more than 20 mL.



 
 

Media Gallary

References

https://pubmed.ncbi.nlm.nih.gov/28301998/

https://www.ncbi.nlm.nih.gov/books/NBK559177/

Hepatocellular Carcinoma

Updated : May 13, 2024




Hepatocellular carcinoma is a primary tumor of the liver that accounts for more than ninety percent of primary liver tumors. It is present in roughly 85% of patients diagnosed with liver cirrhosis, hepatocellular carcinoma.

Hepatocellular Carcinoma is currently the fifth leading cause of cancer throughout the world. It is also the second most common cause of cancer death among males following lung cancer. HCC has a five-year survival rate of 18 percent, second only to pancreatic cancer.

Risk factors for Hepatoceullar Carcinoma are:

  • Hepatitis B and C
  • Non-alcoholic fatty liver disease
  • Alcoholic liver disease

80-90% of cirrhotic patients develop Hepatocellular Carcinoma. 2-4% of people with cirrhosis develop HCC each year.

Hepatocellular carcinoma (HCC) is currently the fifth most prevalent cause of cancer globally.   In 2018, almost 841,000 new cases of HCC were identified. In 2018, 780,000 deaths were attributed to HCC.

HCC is three times more prevalent in men than in women.  More than 80 percent of new instances of HCC occur in developing nations with high rates of hepatitis B infection, such as Sub-Saharan Africa, South-East Asia, and China. Non-Alcoholic Fatty Liver Disease is now the major cause of HCC in the globe, particularly in western nations.

Between 2016 and 2030, the incidence of HCC is projected to increase by 122 percent in the US due to the increasing incidence of obesity and diabetes. The median age of Hepatocellular Carcinoma patients in the United States is 64 years. Currently, the majority of people who have been diagnosed with HCV infections were born between 1945 – 1965.

Cirrhosis is a crucial phase in the viral carcinogenesis of hepatocellular cancer. HBV oncogenesis is primarily caused by the integration of the hepatitis B viral genome into the host genome. The insertion of viral DNA into telomerase reverse transcriptase (TERT) promoter regions in the human genome, resulting in mutation, is responsible for 60% of all instances of head and neck cancer.

Other genetic changes include mutations in TP53 (affecting the cell cycle), beta-1 catenin (CTNNBI), axis inhibitor-1 (AXINI), AT-rich interaction domain-containing protein 1A (ARID1A), and ARID2 (chromatin proliferation).

Chronic hepatitis C virus infection, followed by fibrosis, necrosis, and regeneration, contributes to the development of HCC. In liver carcinogenesis, viral structural and non-structural proteins such as NS3, NS4A, NS4B, NS5A, and NS5B serve as molecular markers. Most patients diagnosed with cirrhosis or in advanced stages of fibrosis have a high occurrence of HCV-associated HCC.

The etiological factors responsible for the development of hepatocellular carcinoma include:

  • Hepatitis B and C
  • Non-Alcoholic liver Steatohepatitis and Non-Alcoholic Fatty Liver Disease
  • Alcoholic liver diseases
  • Aflatoxins
  • Glycogen Storage Disease
  • Alagille Syndrome
  • Acute Intermittent Porphyrias
  • Iron Overload
  • Wilson Disease
  • Alpha one Antitrypsin Disease
  • Hypercitrullinemia

Viral Hepatitis:

The chronic hepatitis B virus and the chronic hepatitis C virus are connected with almost 70% of hepatocellular cancer cases. Hepatitis B virus (HBV) is an enclosed, partially double-stranded, circular DNA virus that is a member of the Hepadnavirus family. Hepatitis B is the most prevalent cause of chronic hepatitis on a global scale, currently affecting over 250 million people.

HBV oncogenesis is primarily caused by the merging of the hepatitis B viral genome into the host genome. The insertion of viral DNA into telomerase reverse transcriptase (TERT) promoter regions in the human genome, resulting in mutation, is responsible for 60% of all instances of head and neck cancer.

Other genetic changes include mutations in TP53 (affecting the cell cycle), beta-1 catenin (CTNNBI), axis inhibitor-1 (AXINI), AT-rich interaction domain-containing protein 1A (ARID1A), and ARID2 (chromatin proliferation).

Hepatitis B and Hepatitis C virus infections account for 56 percent and 20 percent, respectively, of HCC cases diagnosed worldwide. Hepatocellular carcinoma can develop in the absence of cirrhosis in individuals infected with hepatitis B. Over 80% of HBV-related HCCs are accompanied with cirrhosis.

Elevated blood HBV DNA levels (equivalent to or greater than 10,000 copies/mL) are a significant risk factor for hepatocellular carcinoma in HBV-positive patients. This is independent of the patient’s hepatitis B e antigen status. Additionally, the presence of hepatitis B e antigen is linked with a higher prevalence of HCC.

This could indicate an extended replication process. HBV genotype C is linked to an increased risk of HCC. Patients with a low hepatitis B viral load but elevated levels of hepatitis B surface antigen with concentrations over 1000 IU/mL are strongly related with HCC. HCC is more likely to develop when an individual is infected with both the hepatitis C virus and the hepatitis delta virus.

Hepatitis C virus (HCV) is a plus-sense, partly double-stranded RNA virus comprising 11 primary genotypes and 15 subtypes. HCC is usually related with HCV genotype 1b.   HCV does not assimilate into the genome of the host. Cirrhosis is an important phase in the viral carcinogenesis of Hepatocellular Carcinoma.

Chronic hepatitis C virus infection, followed by fibrosis, necrosis, and regeneration, contributes to the development of HCC. In liver carcinogenesis, viral structural and non-structural proteins such as NS3, NS4A, NS4B, NS5A, and NS5B serve as molecular markers.

The majority of patients with cirrhosis or advanced stages of fibrosis develop HCV-associated HCC. In patients without cirrhosis, fewer instances of HCV-related HCC have been recorded.  20% of all HCC cases identified globally are caused by Hepatitis C. There is a greater risk of incidence if an individual is also infected with Hepatitis B.

Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Liver Steatohepatitis

Non-alcoholic fatty liver disease is characterized by an excess amount of fat in the hepatocytes, without the presence of alcohol consumption. NAFLD is typically associated with metabolic syndrome. Conditions such as insulin resistance, hypertension, hypertriglyceridemia, and abdominal obesity are associated with the metabolic syndrome, which raises cardiovascular risk.

NAFLD is now the major cause of HCC in the globe, particularly in western nations. 13% of individuals diagnosed with HCC without cirrhosis were also diagnosed with NAFLD.

Alcohol and Alcoholic Liver Diseases

In the United States, 30% of head and neck cancers are linked to a background of excessive alcohol consumption. Alcohol can cause HCC both directly and indirectly. Through cirrhosis, alcohol can indirectly induce liver cancer. Increased alcohol consumption increases oxidative stress and inflammation. Consuming more than 80 g of alcohol each day multiplies the risk of HCC by five.

Aflatoxins

Mycotoxin Aflatoxin B1 is generated by the fungi Aspergillus flavus and Aspergillus parasiticus. These fungi are prevalent in Sub-Saharan Africa and Southeast Asia, where they contaminate grains. The primary cause of carcinogenesis seems to be mutations in tumor suppressor genes (p53). Aflatoxin B1 is connected with an increased incidence of HCC in patients suffering with chronic Hepatitis B.

There are over 6 accepted staging systems used to determine the survival rates for Hepatocellular Carcinoma.

All of these systems take into account the following 4 prognostic factors:

  • Size and quantity of tumor
  • The extent of spread of the tumor
  • Presence of metastases
  • Severity of accompanying liver disease

It is challenging to successfully stage individuals with hepatocellular carcinoma due to the numerous variables. Therefore, there is no optimal system that is ideal for predicting survival rates.

As a rule of thumb, treatment for each should be personalized patient and not based on an algorithmic approach, since aggressive treatments are generally effective for certain patients with HCC. A multidisciplinary approach is suggested for achieving better outcomes.

regorafenib

40

mg

Tablet

Oral

4 times a day

The medication is continued until the disease is reduced to acceptable toxicity



Dose Adjustments

In case of adverse reactions, the dose is modified or reduced First dose reduction: 120 mg total daily Second dose reduction: 80 mg daily In case the patient is unable to tolerate 80 mg daily, discontinue the treatment

sorafenib

400

mg

Tablet

Oral

every 12 hrs

In case of toxicity of the skin, reduce or discontinue the dose



doxorubicin

CTACE intra-arterial:

50 - 75

mg/m^2

Intravenous (IV)

as a single dose via intra-arterial injection every 2 months for a maximum of 3 doses.
DEB-TACE intra-arterial: 150 mg administered via loaded drug-eluting bead every 2 months for a maximum of 3 doses.



ramucirumab (Rx)

8

mg/kg

Solution

Intravenous (IV)

every 2 weeks

1

hr



cabozantinib

60

mg

orally

once a day

The treatment needs to be continued until disease progression or unacceptable toxicity occurs



atezolizumab

1200

mg

Intravenous (IV)

over 1 hr

and followed by 15 mg per kg of bevacizumab on the same day for every three weeks
Continue the course until disease progression, or unacceptable toxicity occurs
if bevacizumab is discontinued for toxicity, the dosage recommended for atezolizumab is:
840 mg given IV every two weeks or 1200 mg given IV every three weeks, or 1680 mg given IV every four weeks
Continue the course until disease progression, or unacceptable toxicity occurs
Note:
the first infusion administered for over 60 minutes if well-tolerated, and subsequent infusions administered for around 30 minutes



ipilimumab

ipilimumab 3 mg per kg given IV over 30 minutes every 3 weeks with nivolumab 1mg per kg given IV over 30 minutes on the same day for 4 doses
After completing four doses of combination, nivolumab is given as a single agent.
Continue the therapy until disease progression or unacceptable toxicity occurs.



lenvatinib 

For <60 kg: 8 mg orally each day
For ≥60 kg: 12 mg orally each day



regorafenib 

regorafenib is indicated in the treatment of hepatocellular carcinoma in patients who have undergone previous treatment with sorafenib
A dose of 40 mg is administered four times daily for initial 21 days of every 28-day cycle
The medication is continued until the disease is reduced to acceptable toxicity



Dose Adjustments

In case of adverse reactions, the dose is modified or reduced
The pattern of dose reduction goes like this
First dose reduction: 120 mg total daily
Second dose reduction: 80 mg daily
In case the patient is unable to tolerate 80 mg daily, discontinue the treatment

bai ji 

6 - 15

g

Orally 

day



ethiodized oil 

Slowly inject 1.5 to 15 mL under continuous radiologic monitoring.
The total dosage should not exceed be more than 20 mL.



https://pubmed.ncbi.nlm.nih.gov/28301998/

https://www.ncbi.nlm.nih.gov/books/NBK559177/