Liver cancer has been one of the leading causes of cancer-related deaths. A recent article in HemOnc Today reports that liver cancer is perhaps one of the most difficult cancers to treat.

Dire projections through 2040 were laid out in an April 7, 2021 article published in JAMA. The article describes an ever-changing landscape. With estimates of 41,000 deaths, intrahepatic bile duct cancer and liver cancer may surpass colorectal cancer.

On a more positive note though, decreases are expected in breast cancer deaths and in prostate cancer incidence.

Is Liver Cancer Two Diseases?

Yes, according to Dr. Robin K. Kelley. Dr. Kelley explains that most patients diagnosed with liver cancer also have an underlying disease. Therefore, both toxicity management and therapy must be addressed.

Dr. Kelley admits the 2040 projections are disturbing. However, there is cause for some optimism. Along with the increase in liver cancer, there has been ongoing progress in therapies.

Working Towards a Breakthrough

Leading oncologists in hepatobiliary cancer (liver, bile duct, and gallbladder) offered their view on the new treatment landscape which includes research on biomarkers, drug combinations, and the next breakthrough.

No treatment existed fifteen years ago that could prolong overall survival for liver cancer patients until the approval of sorafenib in 2007. This was a first for systemic hepatocellular carcinoma (HCC) therapy.

The phase III trial investigating sorafenib involved 602 patients diagnosed with advanced liver disease. The patients who were treated with sorafenib exhibited a forty-four percent increase in overall survival compared to patients who received a placebo.

The Ten Years That Followed

Although the approval of sorafenib was exciting and motivating, progress during the next ten years was discouraging.

Some of the drugs, such as sunitinib, were rejected because the drug was too powerful and therefore toxic. Other drugs proved not to be powerful enough.

A Tidal Wave of Drugs

One of the oncologists termed the period from 2017 through  2020 as being a tidal wave of drug approvals for HCC. A brief list of newly approved drugs from that period follows:

• Regorafenib (Stivarga) blocks enzymes that cause cancer growth
• Lenvatinib (Lenvima) is a monotherapy for HCC when cancer cannot be removed by surgery (unresectable)
• Cabozantinib (Cabometyx) and ramucirumab (Cyramza), both multi-kinase inhibitors
• Nivolumab (Opdivo) is an anti-PD-1 antibody
• Pembrolizumab (Keytruda) is an anti-PD-1 antibody
• Ipilimumab (Yervoy) is a CTLA-4 antibody plus Nivolumab

The latter three drugs received accelerated approval and are under FDA review.

Cold and Hot Tumors

The immune system can identify a “hot” tumor, but “cold’ tumors escape notice. Vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR) is able to turn “cold” tumors into “hot” tumors, producing a greater effect for immune checkpoint inhibitors such as Yervoy, Keytruda, and Opdivo. The new “hot” tumors will now have considerable difficulty hiding from the immune system. Survival has been long, lasting beyond twelve months and into the twenty month-range.

About Biomarkers

Dr. Kelley explained that therapy selection is challenging due to the fact that there are few established biomarkers for HCC. A biomarker is a measure that indicates treatment outcome such as a blood pressure reading.

Currently, there is an urgency to identify biomarkers that will predict how patients will respond to treatment with checkpoint inhibitors.

Looking Forward

Pharmaceutical companies are racing to develop drugs that will control the increase in nonalcoholic steatohepatitis and nonalcoholic fatty liver disease. Both diseases are obesity-associated disorders.  The concern is that without drugs to contain the diseases, the numbers will continue to increase unabated.

Dr. Kelley and associates co-authored an article published in a January edition of Nature Reviews Disease Primers. The article outlines several trials that are investigating various combination therapies that will greatly affect managing HCC at all levels.

Socioeconomic Disparities

Of great concern are the underrepresented HCC patients who face socioeconomic disparities. Dr. Kelley said that tumors are not the only challenge, it is discrimination. Many HCC patients do not have sufficient insurance and cannot receive proper treatment. She asked for a team effort to give these patients a better chance at improving the outcome of their disease.

Treatments Have Improved But the Key is Detecting Liver Cancer Early

Doctors who spoke with HemOnc Today were pleased with the recent progress in treating liver cancer when it is in the advanced stages.

However, their primary focus was finding liver cancer early. One doctor explained that early detection is the difference between treating the patient or actually curing the patient. He said that in eighty percent of patients with liver cancer, cancer began with liver disease.

One potential breakthrough would be the ability to use liquid biopsy which, if perfected, could detect the tumors earlier. Using blood biomarkers to identify tumors under 2 cm would, in ninety percent of cases, translate to a cure.

The doctors see an urgent need to stress the importance of screening patients with chronic liver disease.

The full HemOnc Today article is available here.