Advances in Liver Cancer Research

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 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. Researchers are testing ways to prevent and treat some of these conditions.

Cirrhosis

The most important risk factor for HCC is cirrhosis, a disease that occurs when scar tissue forms in the liver and prevents it from working correctly. NCI’s HCC Early Detection Strategy Study, a long-term study that followed people with cirrhosis, found that about 2 to 3 of every 100 people developed the disease each year.

Through NCI’s Cancer Prevention Clinical Trials Network, several studies have tested whether drugs used to treat other diseases can prevent cirrhosis from advancing to liver cancer. For instance, a study found the best dose of a cancer drug called erlotinib (Tarceva) for follow-up studies on the prevention of liver cancer. Another study, awaiting results, tested green tea polyphenols. And an ongoing study is testing a cholesterol-lowering medication (statin).

Metabolic Dysfunction-associated Steatohepatitis (MASH)

MASH (formerly called nonalcoholic steatohepatitis or NASH) is a common liver disease that can cause cirrhosis and may lead to liver cancer. MASH is the most severe form of nonalcoholic fatty liver disease, where there is more fat than normal in the liver. In 2021, a clinical trial showed that the weight loss drug semaglutide resolved MASH in most patients.

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, which can only be contracted by people infected with hepatitis B virus, may also increase the risk of HCC. Vaccination again hepatitis B virus also prevents infection with hepatitis D virus. NCI's Liver Cancer Program recently completed a study in Mongolia that helps explain how infection with the hepatitis D virus increases risk of HCC among people infected with hepatitis B virus.

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.

Sex Hormones

In the US, liver cancer is more likely to be diagnosed in men than women, but scientists don’t know why. In a large study looking at blood tests from more than 380,000 people, NCI researchers found that higher levels of both androgens and estrogens were linked with liver cancer in men. These findings add to evidence from an earlier NCI study that looked at sex hormones and HCC risk among women. Research is underway to explore how sex hormones might influence liver cancer risk. 
 

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. Several imaging and blood tests are being studied to see if they can detect liver cancer at an early stage, especially among people who are most at risk for liver cancer. 

Screening and Surveillance

The National Liver Cancer Screening Trial is an NCI-supported clinical trial comparing two kinds of liver cancer screening tests in more than 5,000 people with cirrhosis or chronic hepatitis B infection. Half of the participants will be screened with an ultrasound exam of the liver plus a test for a blood-based biomarker called alpha-fetoprotein. The other participants will get screening with a test called GALAD, which takes into account levels of three blood-based biomarkers, plus the person’s age and sex.

People who have liver diseases like cirrhosis or NASH and are at increased risk of getting HCC often receive regular ultrasound exams of the liver, sometimes with a blood test for alpha-fetoprotein. This close monitoring is often referred to as liver cancer surveillance. 

There are many challenges with surveillance tests. For example, doctors cannot always tell which patients are at high risk for HCC and may benefit from surveillance. The test results are not always accurate. There is also a financial burden associated with surveillance. Sometimes it is hard for people to get to a clinic for the tests. Likely, as a result of those challenges, there is mixed evidence on whether having these tests regularly prevents people from dying of liver cancer.

Researchers from NCI's Translational Liver Cancer (TLC) Consortium are working to improve early detection of liver cancer. In one study, TLC-supported researchers are evaluating ways to identify which people with cirrhosis are at highest risk of HCC. They are also trying to determine how best to monitor people at higher risk, such as those with small liver masses. Another TLC-supported study is exploring whether the combination of MRI and a blood test called a liquid biopsy can detect HCC in people with cirrhosis. TLC-supported researchers are also using machine learning to combine multiple factors and predict HCC risk in people with cirrhosis.

Imaging

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

For example, NCI scientists are testing the use of a radioactive substance, called a radiotracer, that may help doctors see specific 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, identified several promising biomarkers of early-stage liver cancer that were further studied in NCI’s HCC Early Detection Strategy Study, a long-term study of people with cirrhosis. Investigators found the biomarkers in blood samples from people who developed liver cancer a year later. It is these biomarkers, along with age and sex, that are being evaluated as a screening test in the National Liver Cancer Screening Trial. 

NCI also led a study of Baltimore 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.

A 2023 study from NCI’s TIGER-LC consortium identified biomarkers in blood that could potentially identify HCC and ICC in people at risk of the diseases. The biomarkers are based on antibodies to various viruses present in blood.

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.

Adjusting Treatment by Risk Group

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–supported 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). 

PHITT includes several different studies (or arms) that are using patients’ risk groups (which reflect how likely a patient's cancer is to come back after treatment) to help guide new treatment approaches:

• 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 by itself or cisplatin with other chemotherapy drugs. The outcomes and side effects of the regimens will be compared. The hope is that treatment with cisplatin alone will be just as effective and will lead to fewer side effects and complications later in life.
• A study to see if one chemotherapy combination is better than another at getting rid of tumors in children with high-risk hepatoblastoma.
• 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

A biomarker is something found in blood or other tissues that serves as a sign of a condition or disease. Prognosis means an estimate of how a disease will affect someone long-term. Doctors can use biomarkers of prognosis to guide treatment decisions.

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.

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.

Fibrolamellar Carcinoma

Fibrolamellar carcinoma, or FLC, is a rare type of liver cancer that usually grows in teens and young adults. Current treatments for fibrolamellar carcinoma include surgery, chemotherapy, and embolization.

A recent study in mice found that a combination of irinotecan and DT2216 showed promise for treating fibrolamellar carcinoma. Irinotecan is a chemotherapy and DT2216 is an experimental drug that gets rid of a protein which helps FLC survive. 

NCI’s Pediatric Early Phase Clinical Trials Network (PEP-CTN) is planning to launch a trial testing irinotecan and DT2216 for people with fibrolamellar carcinoma. The clinical trial will first find safe doses of both medications when given together in children with solid tumors. The next part of the trial will enroll only patients with relapsed (came back after previous treatment) or refractory (was unaffected by previous treatment) fibrolamellar carcinoma to see if the drug combination can shrink their tumors.