Advances in Liver and Bile Duct 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 bile duct cancer that occurs in parts of the bile ducts within in the liver (also called intrahepatic cholangiocarcinoma, or ICC). HCC is the most common form of liver cancer among adults in the United States. 

More people in the United States are developing HCC and ICC than ever before . Researchers are trying to find out why.

Several conditions can increase your chances of developing HCC and ICC. 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. However, only 3% to 5% 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 green tea polyphenols, cholesterol-lowering medications (statins), and low doses of a cancer drug called erlotinib (Tarceva).

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.

People with chronic hepatitis C infections may be treated with drugs that attack the hepatitis C virus, called direct-acting antivirals. These drugs can help prevent a chronic hepatitis C infection from leading to HCC. Findings from a recent NCI-funded study suggest that treatment with direct-acting antivirals improves the survival of people with hepatitis C-related HCC.

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 of the bile ducts (primary sclerosing cholangitis) increase your 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, surgery plus liver transplantation, or treatments such as radiofrequency ablation. Researchers are working to develop tests that better detect early-stage liver cancer. They are also trying to figure out who is most at risk for liver cancer and most likely to benefit from these tests.

Surveillance

Liver cancer surveillance means closely monitoring someone who is more likely to get HCC. During surveillance, screening exams and tests like an ultrasound of the liver, or a blood test for a protein called alpha-fetoprotein, are done on a regular schedule.

There are many challenges with these surveillance strategies, and they do not appear to prevent people from dying of liver cancer. For example, it's hard for doctors to know which patients are at high risk for HCC and may benefit from screening. Plus, the available screening tests 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. For example, TLC-supported researchers are exploring whether electronic medical records could be used to alert both doctors and patients when a patient is due for their next screening test.
• Another TLC study is exploring how to make HCC surveillance more personalized by matching individuals with different screening 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, people with cirrhosis caused by nonalcoholic fatty liver disease (NAFLD) or other liver diseases are given screening tests twice a year. NAFLD, a condition in which fat builds up in the liver, can sometimes progress to 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

Detecting small, early-stage liver tumors with an ultrasound exam is challenging, especially for people who are obese or have 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.

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 developed liver cancer.

NCI also led a study of Baltimore, MD residents to explore genetic features of liver cancer and to find biomarkers for early detection or prevention.

Liver Cancer Treatment

Liver cancer is often diagnosed at an advanced stage. Treatment options for advanced liver cancer include targeted therapy, immunotherapy, radiation, embolization, and ablation.

Targeted Therapy

Targeted therapies are drugs or other substances 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.

Several other targeted therapies have been approved to treat people with HCC that has stopped responding to sorafenib, including:

• Regorafenib (Stivarga)
• Cabozantinib (Cabometyx)
• Ramucirumab (Cyramza)

Another targeted therapy, lenvatinib (Lenvima), is now used to treat people whose liver tumors can’t be removed by surgery.

But 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 Bile Duct Cancer

People with bile duct cancer can also be treated with targeted therapies.

• Pemigatinib (Pemazyre) and infigratinib (Truseltiq) are FDA approved for adults with bile duct cancer 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 cholangiocarcinoma. 
• Other clinical trials are testing new targeted therapies for people with bile duct cancer 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 bile duct cancer cells have changes in the IDH1 or IDH2 genes.

Immunotherapy

Immunotherapy for HCC

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

• Nivolumab (Opdivo) alone or with ipilimumab (Yervoy)
• Pembrolizumab (Keytruda) 
• Atezolizumab (Tecentriq) in combination with bevacizumab (Avastin) for liver cancer that has spread or that can't be treated with surgery.

For advanced HCC, a recent clinical trial showed that a combination of two immunotherapies (tremelimumab and durvalumab) was more effective than sorafenib. The study also showed that durvalumab alone was equally as effective as sorafenib.

Immunotherapy for Bile Duct Cancer

Scientists are also researching new ways to use immunotherapy to treat bile duct cancer. For example:

• In a small clinical trial of patients 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.
• Another clinical trial of people with advanced bile duct cancer tested a different immunotherapy (durvalumab) plus chemotherapy (gemcitabine and cisplatin). The immunotherapy plus chemotherapy helped people live longer than chemotherapy only.
• 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 CD40-ligand. The researchers are hoping to launch a clinical trial of the combination for people with ICC.

Some examples of ongoing immunotherapy research in liver cancer include:

• NIH's Liver Cancer Program has launched a study to identify characteristics that influence how a patient’s liver cancer responds to immunotherapy. The study aims to examine tumors from 500 patients with primary liver cancer who took part in immunotherapy clinical trials. The researchers have found that people with liver cancer cells that are all alike are more likely to respond to immune checkpoint inhibitors than people with liver cancer cells that are diverse. A related study by NCI scientists may explain why: Cancer-killing immune cells were less active in tumors with diverse liver cancer cells.
• NCI’s Immuno-Oncology Translational Network (IOTN) has an ongoing study to explore how the immune system interacts with liver tumors as they develop and what makes some liver tumors more sensitive to treatment with immune checkpoint inhibitors.
• An ongoing NCI-sponsored clinical trial is testing a CAR T-cell therapy for adults with advanced liver cancer. The therapy involves removing a person’s own immune cells and modifying them in a lab so they can better see liver cancer cells. The goal of the trial is to see if the new therapy is safe.

Radiation Therapy

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

One trial is comparing proton therapy to standard photon therapy for people with HCC that cannot be removed by surgery. Proton therapy is a new kind of radiation therapy that may cause less harm to healthy tissues. People who have liver cancer and another liver disease may be able to tolerate the effects of proton therapy more than those of standard photon therapy.

The other trial is testing the combination of the targeted therapy 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. The combination will be compared with sorafenib on its own.

Transarterial Therapy

People with advanced liver cancer can be treated with therapies that are put directly into the blood vessels that feed their tumors. For example, transarterial therapy, also called transarterial embolization, involves placing small beads into the 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.

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 new study shows 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 precise biology of their tumor.

Biomarkers that are found in tumor tissue (sometimes called tumor markers) may aid precision medicine approaches for liver cancer treatment. For instance, scientists are looking for biomarkers in HCC tumors that may help predict whether a given treatment is likely to work for an individual patient. These biomarkers could help doctors select tailored treatments for patients with HCC.

Investigators in NCI’s Center for Cancer Research are also studying the molecular features of liver tumors in detail to try to identify new drug targets and small groups of liver tumors that share similar features (called cancer subtypes). Defining more-detailed liver cancer subtypes may help guide more precise treatments for people with this disease.

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 liver cancer is.

Childhood and Adolescent Liver Cancer Treatment

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

Because childhood and adolescent liver cancer is relatively 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

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 after 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 children who have had surgery to remove HCC tumors benefit from receiving chemotherapy after surgery.

Biomarkers of Prognosis

When a child is diagnosed with hepatoblastoma, their tumor tissue is often examined under a microscope. If the tumor tissue has a specific pattern, called small cell undifferentiated (or SCU), experts used to think the cancer was more aggressive. But a 2021 Children’s Oncology Group-led study actually found that children with SCU hepatoblastomas lived just as long as those without SCU.

PHITT also aims to identify biomarkers that indicate a child’s or adolescent’s 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 potential biomarkers of prognosis. If these biomarkers are found to be accurate, the researchers will use them in future studies of new therapeutic approaches.

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, it is unclear whether these factors are responsible for the increase in liver cancer incidence in the United States. 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 who drink coffee have a lower 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?
• 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.