Advances in Liver Cancer Research

Prevention of Liver Cancer

There are several types of liver cancer in adults. The two most common types are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). ICC is cancer that occurs in parts of the bile ducts within in the liver. It is sometimes considered a type of bile duct cancer.

HCC is the most common form of liver cancer among adults in the United States. The survival rates of both HCC and ICC are low.

Several conditions can increase your chances of developing HCC or ICC. (For a full list of risk factors for HCC and ICC, see our page on Liver and Bile Duct Cancer.) Researchers are testing ways to prevent and treat some of these conditions.

Cirrhosis

The biggest risk factor for HCC is cirrhosis, a disease that occurs when scar tissue forms in the liver and prevents it from working correctly. Less than 10% of people with cirrhosis will develop HCC.

Through NCI’s Phase 0/I/II Cancer Prevention Clinical Trials Program, several studies are testing whether drugs used to treat other diseases can prevent cirrhosis from advancing to liver cancer. Drugs that are being tested include cholesterol-lowering medications (statins), low doses of a cancer drug called erlotinib (Tarceva), and green tea polyphenols.

Hepatitis Virus Infection

Another common risk factor for HCC is chronic infection with hepatitis B virus or hepatitis C virus. Infection with hepatitis B virus can be prevented by vaccination. There is no vaccine for hepatitis C virus, but researchers are working on developing and testing one.

Chronic infection with hepatitis D virus may also be a risk factor for HCC. NIH's Liver Cancer Program recently completed a study of Mongolian patients that helps explain how infection with the hepatitis D virus might cause liver cancer.

Inflammation

Inflammation of the colon (colitis) and inflammation of the bile ducts (primary sclerosing cholangitis) increase the chances of developing ICC. NCI researchers recently found preliminary evidence that these conditions may make gut bacteria leak into the liver, leading to a buildup of certain immune cells that help ICC grow. Scientists think that blocking these gut bacteria or immune cells might be a way to prevent ICC.

Early Detection of Liver Cancer

Liver cancer that is diagnosed at an early stage has a good chance of being cured with surgery, liver transplantation, or treatments such as radiofrequency ablation. There are no standard screening tests for liver cancer, but several imaging and blood tests are being studied to see if they can detect liver cancer at an early stage, especially among those who are most at risk for liver cancer 

Surveillance

Liver cancer surveillance means closely monitoring someone who has an increased chance of getting HCC. Someone having surveillance may get regular ultrasound exams of the liver, sometimes with a blood test for alpha-fetoprotein.

There are many challenges with these surveillance strategies, and they have not been found to prevent people from dying of liver cancer. For example, doctors cannot always tell which patients are at high risk for HCC and may benefit from surveillance. 

There is also a financial burden associated with surveillance. Sometimes it is hard for patients to get to a clinic for the tests. Plus, the tests for liver cancer surveillance are not always accurate. 

However, scientists are looking at ways to address these problems. For example:

• Researchers from NCI's Translational Liver Cancer (TLC) Consortium are working to improve surveillance and early detection. In one study, TLC-supported researchers are exploring whether electronic medical records could be used to alert both doctors and patients when a patient is due for a liver ultrasound or alpha-fetoprotein test.
• Another TLC study is exploring how to make HCC surveillance more personalized by matching people with different surveillance tests depending on their level of liver cancer risk.
• A third TLC-supported study aims to find a way to predict which patients with cirrhosis will develop liver cancer. In this study, researchers are using machine learning to combine multiple factors and predict HCC risk in people with cirrhosis.
• In 2020, NCI scientists developed a blood test that, in a small study, correctly pinpointed people with chronic liver disease (including cirrhosis) who later developed HCC. The blood test was able to pick out those who developed HCC even 10 years before their cancer was diagnosed. The scientists are continuing to study how the blood test works.

Imaging

Small, early-stage liver tumors can be difficult to detect on an ultrasound exam, especially for people have obesity or cirrhosis. Scientists are developing new kinds of imaging tests that may be better at detecting small tumors.

For example, one group of TLC-funded researchers is using small molecules, called peptides, that attach to liver cancer cells. These peptides are linked to dyes that can be seen with a CT scan or MRI.

NCI scientists are also testing a radioactive substance, called a radiotracer, that may help doctors see certain parts of the body. The scientists are learning if the radiotracer may be better able to find HCC than standard imaging. 

Biomarkers

A biomarker is a molecule found in blood or other tissues that serves as a sign of a condition or disease. Scientists are working to find biomarkers in blood, urine, or other body fluids that are reliable signs of early-stage liver cancer.

Scientists in NCI’s Early Detection Research Network (EDRN), a network of institutions researching biomarkers for early-stage cancer, have identified several promising biomarkers of early-stage liver cancer.

These biomarkers are being further studied in NCI’s HCC Early Detection Strategy Study, a long-term study of people with cirrhosis. Investigators are looking to see if these biomarkers are found in blood samples from people who later develop liver cancer.

NCI is also leading a study of Baltimore, MD residents to explore genetic features of liver cancer and to find biomarkers for early detection or prevention. Using data from this study, NCI researchers found several potential biomarkers of HCC.

Liver Cancer Treatment

Liver cancer is often diagnosed at an advanced stage. Treatment options for advanced liver cancer include chemotherapy, targeted therapy, immunotherapy, radiation, embolization, and ablation. For more information on treatment options, see our page on liver cancer treatment.

Targeted Therapy

Targeted therapies are drugs that attack molecules that help cancer cells grow, divide, and spread.

Targeted Therapy for HCC

For many years, sorafenib (Nexavar) was the only targeted therapy available for people with advanced HCC. But research has led to the discovery of several newer targeted therapies for HCC. 

However, even with these new treatments, most people with HCC don't live for more than 5 years after being diagnosed. So, better treatments are still needed.

Targeted Therapy for ICC

New research has led to FDA approval of several targeted therapies for people with ICC. In addition, ongoing research is testing whether other targeted therapies work for ICC:

• A clinical trial tested the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) on adults with advanced cancer, including ICC, that has a specific mutation in the BRAF gene. The study helped lead to FDA approval of this drug combination in 2022. Around 5% of people with ICC have the specific BRAF mutation.
• FDA has also approved another targeted therapy for ICC called futibatinib (Lytgobi). It is approved for adults with ICC whose cancer cells have a genetic change that fuses the FGFR2 gene to another gene. Around 15% of people with ICC have such a genetic change. 
• Two ongoing clinical trials are comparing pemigatinib and infigratinib (separately) with standard chemotherapy for people who are newly diagnosed with ICC or cancer of the bile ducts outside of the liver (extrahepatic cholangiocarcinoma). 
• Other clinical trials are testing new targeted therapies for people with ICC who have specific gene changes in their cancer cells. For example, studies are testing targeted therapies such as olaparib (Lynparza) and LY3410738 in people whose ICC or extrahepatic cholangiocarcinoma cells have changes in the IDH1 gene or IDH2 gene.

Immunotherapy

Immunotherapy for HCC

Immunotherapy is now a standard treatment for people with HCC. Several immune checkpoint inhibitors are currently approved to treat HCC.

In 2022, FDA approved a combination of the immunotherapies tremelimumab (Imjudo) and durvalumab (Imfinzi) for people with HCC that can’t be removed by surgery. A clinical trial showed that this combination was more effective than sorafenib alone.

Immunotherapy for ICC

Immunotherapy is a standard treatment for people with ICC. Scientists are also researching new ways to use immunotherapy to treat ICC. For example:

• A clinical trial of people with advanced bile duct cancer, including ICC, compared immunotherapy (durvalumab) plus chemotherapy (gemcitabine and cisplatin) with chemotherapy alone. The immunotherapy-plus-chemotherapy combination helped people live longer and was FDA approved in 2022. It is now a standard treatment for people with ICC.
• In a small clinical trial of people with advanced bile duct cancer, NCI researchers showed that an immunotherapy (pembrolizumab) plus two chemotherapy drugs (capecitabine and oxaliplatin) shrank or stopped the growth of tumors in more than 80% of patients.
• In a 2021 study of mice with ICC, NCI researchers saw promising results with a combination of two immunotherapy drugs—an immune checkpoint inhibitor and a drug called a CD40 ligand. The researchers are hoping to launch a clinical trial of the combination for people with ICC.
• NCI researchers have also found that people whose HCC or ICC cells that are molecularly similar to each other are more likely to respond to immunotherapies than people whose HCC or ICC cells are diverse. A related study by NCI scientists may explain why: Cancer-killing immune cells were less active in tumors with diverse HCC or ICC cells.

Some examples of ongoing immunotherapy research in liver cancer include:

• Studying why immunotherapies only work for some people with liver cancer. NIH's Liver Cancer Program has recently identified molecular characteristics linked with survival after immunotherapy treatment for HCC or ICC.
• NCI’s Immuno-Oncology Translational Network (IOTN) is exploring how the immune system interacts with HCC tumors as they develop and what makes some HCCs more sensitive to treatment with immune checkpoint inhibitors.
• An NCI-sponsored clinical trial testing a CAR T-cell therapy for adults with advanced HCC. The therapy involves removing a person’s own immune cells and modifying them in a lab so they can better recognize and attack HCC. The goal of the trial is to see if the new therapy is safe.
• An NCI-sponsored clinical trial testing an investigational immunotherapy drug called M9241 in combination with chemotherapy for adults with ICC. 

Radiation Therapy

NCI’s National Clinical Trials Network (NCTN) is currently supporting two ongoing clinical trials of radiation therapy for people with HCC that cannot be removed with surgery.

• One trial is comparing proton therapy with standard photon therapy. Proton therapy is a new kind of radiation therapy that may cause less harm to healthy tissues.
• The other trial is testing sorafenib with a type of radiation therapy called stereotactic body radiation therapy. This approach uses special equipment to position the patient and precisely deliver radiation directly to the tumor, which may cause less harm to the rest of the body. Early findings have shown that sorafenib with stereotactic body radiation therapy is more effective than sorafenib alone.

Transarterial Therapy

Some therapies can be put directly into the blood vessels that feed liver tumors. For example, transarterial therapy, also called transarterial embolization, involves placing small beads into blood vessels to cut off blood flow to the tumor.

Researchers are exploring ways to enhance transarterial therapy, such as using radioactive beads that not only block blood flow but also deliver radiation to the tumor. These therapies are also being studied in combination with targeted therapies and with immunotherapies.

For instance, an NCI-led clinical trial is testing a type of transarterial embolization called TACE plus two immunotherapies (tremelimumab and durvalumab) and a targeted therapy (bevacizumab) as a treatment for people with HCC.

Transplantation

Some people with early-stage liver cancer can be cured with a liver transplant. Currently, only patients with a few small tumors in their liver can get a liver transplant. But a 2022 study found that patients who first get treatment to make their tumors smaller can also be cured by a liver transplant.

Precision Medicine

Precision medicine is an approach to patient care that allows doctors to select treatments that are most likely to help patients based on the biology of their tumors.

Biomarkers that are found in tumor tissue (sometimes called tumor markers) may aid precision medicine approaches for liver cancer treatment.

For instance, investigators in NCI’s Center for Cancer Research are studying liver tumors in finer detail to try to identify molecular features that can help guide treatment decisions or lead to more-precise treatments.

For example, a 2021 study from NCI’s TIGER-LC consortium identified biomarkers in blood that could potentially help doctors determine how aggressive a patient’s HCC is.

Childhood and Adolescent Liver Cancer Treatment

Several types of liver cancer can develop in children and adolescents. The most common types are HCC and hepatoblastoma. Adolescents are more likely to develop HCC than younger children. Standard treatments for children or adolescents with liver cancer include surgery, chemotherapy, radiation therapy, and ablation therapy.

Because childhood and adolescent liver cancer is fairly rare, randomized clinical trials of new treatments can be a challenge to conduct. The Children’s Oncology Group, part of the NCI–sponsored National Clinical Trials Network, is collaborating with other institutions on the first randomized international trial for children with liver cancer, called the Pediatric Hepatic International Tumor Trial (PHITT). The trial aims to enroll more than 1,000 patients with hepatoblastoma and about 200 patients with hepatocellular carcinoma. This trial will test treatments that are adjusted by risk group and look for biomarkers of prognosis.

Adjusting Treatment by Risk Group in PHITT

PHITT includes several different studies that are using patients’ risk groups to help guide new treatment approaches. A risk group reflects how likely a patient’s cancer is to come back after treatment. The trial involves multiple studies (or arms) including:

• One study testing whether fewer cycles of cisplatin, which can cause hearing loss at its standard dose, can effectively treat children with low-risk hepatoblastoma who have already had surgery to remove their tumors.
• A study randomly assigning children with intermediate-risk hepatoblastoma to receive cisplatin alone or cisplatin in combination with other chemotherapy drugs. The outcomes and side effects of the regimens will be compared. The hope is that less exposure to toxic drugs will lead to fewer side effects and complications later in life.
• A study randomly assigning children with high-risk hepatoblastoma to receive one of two different combinations of chemotherapy to see if one combination is better than the other.
• A study testing whether adding gemcitabine and oxaliplatin to standard chemotherapy benefits children and adolescents who have HCC that can’t be surgically removed (unresectable) or has spread beyond the liver (metastatic). 

Biomarkers of Prognosis

PHITT also aims to identify biomarkers of prognosis. Trial researchers are collecting samples of participants’ blood, healthy tissue, and cancer tissue to create the world's largest repository of biological samples from children and adolescents with liver cancer.

By studying these samples, scientists have identified several potential biomarkers. These biomarkers could one day be used to guide treatment decisions for patients with hepatoblastoma.

A specific pattern in the tumor tissue of children with hepatoblastoma, called small cell undifferentiated (or SCU) histology, was once thought to be a biomarker of an aggressive cancer. But a 2021 Children’s Oncology Group-led study found that children with SCU hepatoblastomas actually lived just as long as those without SCU.

NCI-Supported Research Programs

Many NCI-funded researchers working at the NIH campus, as well as across the United States and throughout the world, are seeking ways to address liver cancer more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer and the social factors that affect cancer risk. And some is more clinical, seeking to translate this basic information into improving patient outcomes. The programs listed below are a small sampling of NCI’s research efforts in liver cancer.

Prevention

The Phase 0/I/II Cancer Prevention Clinical Trials Program conducts early-phase clinical trials of interventions that have the potential to prevent cancer, including liver cancer.

The Liver Cancer Pooling Project (LCPP) is an effort to pool data from different sources to study potential causes of liver cancer. Although there are several known risk factors for liver cancer, not all liver cancers are related to known causes. NCI investigators also use LCPP data to study factors that may protect people from developing liver cancer. For example, a study from LCPP found that people with higher levels of sex hormones (like testosterone) in their blood had a higher risk of developing HCC.

The Thailand Initiative for Genomics and Expression Research in Liver Cancer (TIGER-LC) is a consortium of researchers and clinicians from NCI and Thailand studying genetic differences between HCC and ICC, the most common form of liver cancer in Thailand. The study is designed to address liver cancer prevention, early detection, and treatment.

Early Detection

NCI’s Translational Liver Cancer (TLC) Consortium supports research to improve the early detection of liver cancer. The goals of the consortium are to better define the risks of developing liver cancer, improve surveillance for people who are at high risk of liver cancer, and improve the detection of early-stage liver tumors.

Treatment

The Liver Cancer Program is a multidisciplinary network of researchers and clinicians from across the NIH who are dedicated to improving the early detection, diagnosis, treatment, and health disparities of liver cancer in adults.

NCI’s Immuno-Oncology Translational Network (IOTN) is a network of researchers who are developing new immunotherapies to treat cancer, including liver cancer.

NCI’s Fusion Oncoproteins in Childhood Cancers (FusOnC2) Consortium, part of the Cancer Moonshot, is studying the cause of fibrolamellar hepatocellular carcinoma (FLC/FLHCC) a type of liver cancer in children, adolescents, and young adults.

Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for liver cancer prevention, screening, and treatment.

Liver Cancer Research Results

The following are some of our latest news articles on liver cancer research:

• Can the New “Omics” on the Block Find Liver Cancer in Blood?
• Seldom-studied immune cells in the liver may be helpful in treating cancer
• Study Tackles Key Questions about Liver Transplants for People with Liver Cancer
• Study Identifies Potential Drug Target to Prevent Some Liver Cancers
• NIH Scientists Develop Blood Test to Help Improve Liver Cancer Screening
• Atezolizumab Plus Bevacizumab Approved to Treat Liver Cancer
• Some Children with Liver Cancer May Need Less Chemotherapy, Study Suggests

View the full list of Liver and Bile Duct Cancer Research Results and Study Updates.