National Cancer Institute funded researchers are working to advance our understanding of how to prevent, detect early, and treat liver cancer in adults. They are also looking for biomarkers that can provide information about liver cancer, such as how aggressive it is or whether it is likely to respond to a particular therapy.
Here are highlights from some of the latest research in liver cancer, including clinical advances that may soon translate into improved care, NCI-supported programs that are fueling progress, and research findings from recent studies.
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). HCC is the most common form of liver cancer among adults in the United States. ICC is a type of liver cancer that occurs in parts of the bile ducts within the liver.
More people in the United States are developing HCC and ICC than ever before but it’s not clear why. Researchers are trying to find the underlying causes for these trends.
Several factors can increase a person’s risk of developing HCC. Researchers are testing preventive and therapeutic strategies for some of these factors.
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, statins (cholesterol-lowering medications), 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, and researchers are actively developing and testing experimental vaccines for hepatitis C virus.
People with chronic hepatitis C infections may be treated with drugs that attack the hepatitis C virus itself, called direct-acting antivirals. These are used to help prevent 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.
Early Detection of Liver Cancer
Liver cancer that is diagnosed at an early stage has a good chance of being cured with surgery alone, surgery and liver transplantation, or nonsurgical 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 means closely monitoring a person who has an increased risk of a disease. During surveillance, screening exams and tests are done on a regular schedule.
Some experts recommend that people who have risk factors for HCC, such as cirrhosis or chronic hepatitis B or C infection, get screened for liver cancer every 6 months. The most common screening test for liver cancer is an ultrasound exam, with or without a blood test that tests for a chemical called alpha-fetoprotein.
However, there are many challenges with these surveillance strategies and they have not been shown to prevent people from dying of liver cancer. For example, it is hard for doctors to identify which individuals are at high risk for HCC and may benefit from screening. Plus, the available screening tests are not always accurate.
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 are an efficient way 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 develop a way to predict liver cancer risk for patients with cirrhosis, regardless of the cause. Nonalcoholic fatty liver disease (NAFLD) is a condition in which fat builds up in the liver. NAFLD can sometimes progress to cirrhosis. In this study, people with cirrhosis caused by NAFLD or other liver diseases are given screening tests twice a year.
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 specifically to cancer cells in the liver. These peptides are linked to dyes that can be seen with a CT scan or MRI.
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 might indicate the presence 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 is also leading a study of Baltimore, MD residents to explore genetic features of liver cancer and to determine whether molecules in people’s blood, urine, or tissues can be used as biomarkers for early detection or prevention.
Liver Cancer Treatment
Targeted therapies are drugs or other substances that attack molecules that help cancer cells grow, divide, and spread.
For many years, sorafenib (Nexavar) was the only targeted therapy available for people with advanced liver cancer.
Several other targeted therapies have recently been approved to treat people whose liver cancer 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.
However, these treatments have not greatly improved how long people live after being diagnosed with liver cancer, so more-effective treatments are still needed.
Immunotherapy is a major focus of liver cancer treatment research. Two immune checkpoint inhibitors, nivolumab (Opdivo) and pembrolizumab (Keytruda), are currently approved to treat liver cancer. Another immune checkpoint inhibitor, atezolizumab (Tecentriq), was recently approved in combination with bevacizumab (Avastin) as a treatment for liver cancer that has spread or that can’t be treated with surgery.
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 1,000 patients with primary liver cancer who took part in immunotherapy clinical trials. The researchers recently found that people with liver cancer cells that are highly similar to one another are more likely to respond to immune checkpoint inhibitors than people with liver cancer cells that are diverse.
- 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.
- Several ongoing clinical trials are testing whether other immune checkpoint inhibitors, including ipilimumab (Yervoy) and tremelimumab, are effective treatments for people with liver cancer.
- Studies are exploring whether other kinds of immunotherapies, such as CAR T-cell therapy and viruses that infect and kill cancer cells (called oncolytic viruses), may work in liver cancer.
- Clinical trials are testing combinations of immunotherapies or immunotherapies with other therapies, especially targeted therapies that block blood vessel growth.
NCI’s National Clinical Trials Network (NCTN) supports two ongoing clinical trials of radiation therapy for people with liver cancer that cannot be treated 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 underlying 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 healthy tissues. The combination will be compared with sorafenib on its own.
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.
Precision medicine is an approach to patient care that allows doctors to select treatments that are most likely to help patients based on the genetic alterations in 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.
Source: National Cancer Institute, cancer.gov, June 2020