Source: Healio Interview
Disclosures: Karasic reports research funding from Bristol-Myers Squibb, Eli Lilly, Halozyme, H3 Biomedicine, Sirtex, Syndax and Taiho and honoraria from Pfizer.
August 04, 2020
5 min read

The debate continues: How to treat early-stage HCC

Source: Healio Interview
Disclosures: Karasic reports research funding from Bristol-Myers Squibb, Eli Lilly, Halozyme, H3 Biomedicine, Sirtex, Syndax and Taiho and honoraria from Pfizer.
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Hepatocellular carcinoma is one of the few cancers in the United States that has been increasing in incidence and mortality rates over the last three decades.

This is primarily due to an increase in fatty liver syndromes and other liver diseases in the general population, as well as late diagnoses in many patients with HCC. Catching the disease in its early stages has remained difficult because of a lack of widespread screening.

Thomas Karasic, MD
Thomas Karasic

If HCC is diagnosed early, it can be treated with an intent to cure. However, the best way to treat early stage disease is still under debate.

Rising HCC incidence

“As other cancers are becoming less common, HCC is actually becoming more common,” Thomas Karasic, MD, assistant professor of medicine at University of Pennsylvania, told Healio. “It used to be not even in the top 10, but now it’s the fifth leading cancer killer in the U.S.”

According to the American Cancer Society, liver cancer incidence rates have more than tripled since 1980. Between 2007 and 2016, the rate increased approximately 2% per year. The death rate from liver cancer increased from 3 per 100,000 in the 1980s to 6.6 per 100,000 between 2013-2017.

About 70% of liver cancer cases in the U.S. may be prevented if certain risk factors, such as excess body weight, heavy alcohol consumption, tobacco smoking, and chronic infection with hepatitis B or C, are avoided.

More widespread screening could also detect HCC earlier and let patients start treatment earlier.

“The only way we find HCC at an early stage is by imaging,” Karasic said. “People with cirrhosis are supposed to get screened, along with those who have hepatitis B and other high-risk populations.”

“Typically, if you wait until there are symptoms, that means it’s advanced because early-stage HCC has no symptoms that would alert you to it,” he added. “If you get lucky and have abdominal pain for another reason, you could get a scan and find it. But unless you are doing active screening, you find it late.”

Current screening practices

About one-third of HCC cases are found early, and those are typically in patients who have known cirrhosis and are getting appropriate screening.

Other high-risk populations include those with chronic hepatitis B, as well as those who have a family history of liver cancer. Screening typically involves ultrasounds of the abdomen every 6 months, sometimes combined with a blood test for alpha fetoprotein (AFP), which is made by many liver cancers.

“Screening with ultrasound can find the cancer early, but it’s not done as widely as it should be in-part because primary doctors are not always aware of screening guidelines for patients with chronic hepatitis or cirrhosis,” Karasic said. “But for patients with cirrhosis, it is just as important as getting a colonoscopy, a mammogram or other established screening programs. So, we need to be making sure doctors are screening their patients for cirrhosis risk factors like hepatitis C or excess alcohol use, referring them for treatment, and using tools such as ultrasound to catch this cancer early."

“Other screening tools include MRIs and AFP blood tests, but using them are more nuanced and rare,” he added.

If HCC is caught in the early stages and there is one tumor that has not invaded blood vessels, there are three potential curative treatments: surgery, ablation or a liver transplant.

Choosing a treatment

Choosing the best treatment for the patient depends on the tumor characteristics as well as the specific disease, Karasic said.

He added that in his practice, if the patient has one tumor and good liver function, then surgery is usually the best option. If the tumor is small – less than 3 cm – then ablation is usually done because it has the same efficacy with less risks. If there are up to three tumors, or the patient has cirrhosis and cannot safely undergo surgery or ablation, then the preferred approach becomes liver transplant.

“The patient does have to wait for an available liver if they need a transplant, but that is somewhat by design,” Karasic said. “Often, we are trying to decide if a liver transplant will be curative.”

“For a very aggressive form of cancer, the answer is usually ‘no,’” he added. “So, there is a minimum of 6 months before they are prioritized for a liver transplant. In that time, we treat the cancer and monitor its behavior to see if it grows and spreads to other parts of the body. If it does spread rapidly, a liver transplant isn’t going to be curative.”

In 2019 both the National Liver Review Board and the liver distribution system based on Acuity Circles began operation and changed the priority scoring system for liver transplants.

The new system de-prioritizes people with liver cancer, Karasic said.

“Patients with liver cancer were getting priority for transplants over people who were very sick with advanced cirrhosis, so the scoring system was changed to try to make it more fair,” Karasic said. “The downside is that fewer patients with liver cancer will now get transplants.”

Another avenue of treatment for HCC is immunotherapy.

Currently, the FDA has approved nivolumab (Opdivo, Bristol-Myers Squibb) or pembrolizumab (Keytruda, Merck) for advanced disease. Recently, the combination of nivolumab in combination with ipilimumab (Yervoy, Bristol-Myers Squibb) after sorafenib (Nexavar, Bayer) for advanced disease was approved.

The combination of atezolizumab (Tecentriq, Genentech) and bevacizumab (Avastin, Genentech) – which is now awaiting FDA approval – prolonged survival compared with standard-of-care sorafenib for patients with unresectable HCC who had not received prior systemic therapy, according to the phase 3 IMbrave150 study published earlier this year.

“Immunotherapy works very well in some patients with HCC, but unfortunately it doesn’t work in many,” Karasic said. “The disease control rate – meaning you get through a scan or two without disease progression – is only about 50% with any immunotherapy. So, half the people don’t benefit at all. About 15% to 20% get shrinkage of the tumor.”

Future research

There are, however, no immunotherapy treatments approved for early-stage disease.

“It’s being looked at in early-stage disease,” Karasic said. “There are adjuvant trials after surgical resection or ablation for several different drugs. We’re trying to see if you can lower the risks for the cancer coming back if you give it post-surgery.”

“There are also combination trials with intermediate stage disease, adding it to radiation of chemo,” he added. “We’re trying to see if that better controls the disease, but right now it’s only approved in advanced disease.”

Overall, Karasic said the rise in incidence and death rates have led to a growing call within the oncologic community for action to research, catch and cure this disease at an earlier stage.

Enthusiasm is growing, but there is still not a lot of philanthropy support,” Karasic said. “I think that has to do with a lower socioeconomic patient population and stigmas related to this because of alcohol use or hepatitis from IV drug use. So, it’s not as well supported as breast cancer or pancreatic cancer where you see robust philanthropic efforts, but overall, awareness of the disease and support for research is growing.” – by John DeRosier


American Cancer Society. Cancer Facts & Figures 2020. Available at: Accessed May 5, 2020.

Qin S, et al. Ann Oncol. 2020;doi:10.1093/annonc/mdy432.060.