Changing Direction on Liver Cancer Trends

It’s not unusual these days to hear good news about various cancer types as novel treatments bring about significant reductions in the rates of new cases and deaths.

Liver cancer, though, has been heading in the other direction. In 2016, the world mourned the loss of legendary musician David Bowie, who reportedly died of the disease. And just a few years prior, it was a major factor in the death of Lou Reed, another influential musician.

But it’s not just rock stars who succumb to liver cancer. This year, about 40,710 people in the United States will be diagnosed with the disease, and it will be responsible 28,920 deaths. Among common cancers, its incidence is increasing at a rate second only to that of thyroid cancer, and liver cancer deaths are rising at the highest rate in this group.

This is particularly troubling to the medical community because it’s tough to catch liver cancer in its early stages, when potentially curative surgery is an option.

“Unfortunately, liver cancer does not commonly have early warning signs. Symptoms of liver cancer often do not appear until it is in its later stages, where it is harder to treat,” says Bassel El-Rayes, M.D., an oncologist at Emory Winship Cancer Institute, in Atlanta. These symptoms include pain in the upper right side of the belly, bloating, loss of appetite, feelings of fullness, weight loss, fatigue, nausea and vomiting, and yellow skin and eyes.

Avoiding risks such as hepatitis and obesity-related fatty liver may be the most effective and straightforward approach to lowering risk. But for those who have developed liver cancer, the good news is that researchers are working to improve existing treatments for the disease — and to develop new ones. In particular, experts say, targeted drugs and immunotherapies look promising.

While most treatments besides surgery are not considered curative, they may delay progression of cancer, and some remissions might be long-lasting.

“There have been many advances in understanding how to treat liver cancer,” says Ghassan K. Abou-Alfa, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center, in New York. “I always tell my patients that this is a very hopeful time.”

TREATING LIVER CANCER

Treatment options are available for people with all stages of liver cancer. Early-stage disease is often treatable with surgery, which offers the best chance of a cure, but advanced stages usually require alternative strategies.

Surgical tumor removal is an option for patients who have a single malignant liver tumor that has not grown into nearby blood vessels. Once the cancer is removed, a healthy liver has the capacity to grow back and, over time, can even regain some of the function it lost when part of it was taken out.

Potential side effects of surgery include bleeding, infections, complications from anesthesia, blood clots and pneumonia. However, newer laparoscopic and roboticassisted surgical techniques typically cause fewer side effects and are associated with faster recovery times. These are options for patients whose liver tumors are not close to main vessels, or who have not had extensive liver surgery in the past.

Liver Transplantation may be an option for any patient whose cancer has not spread beyond the liver, or for many whose livers are cirrhotic. To be considered eligible, a patient must have either a) a single tumor that is 5 cm or smaller, or b) three or fewer tumors, none of which is larger than 3 cm. However, researchers are investigating the possibility of expanding the criteria for liver transplantation. Liver donors are rare and the wait lists can be long, so transplantation is not always an option, even for those who meet the eligibility criteria.

Possible side effects of this procedure include failure of the bile ducts, blood clots or bleeding, infection and the body’s rejection of the donated organ. High-energy radiation can kill cancer cells and shrink tumors. External beam radiation therapy uses a machine outside the body to deliver the radiation to liver tumor(s).

In internal radiation therapy, also known as brachytherapy, radioactive material is injected into or near the tumor(s). The radiation doesn’t travel far, so it’s less likely to damage nearby normal tissues.

Side effects associated with liver radiation can include skin irritation, stomach upset, low blood counts and fatigue.

Some cancer centers offer minimally invasive techniques that are particularly useful if surgery is not an option, and these may also be administered by a radiation oncologist. One is ablation, which kills small tumors by cutting, vaporizing, melting or using intense heat or cold; this may be done in combination with surgery, or without any surgery at all. Side effects can include infection and internal bleeding. Another minimally invasive technique is NanoKnife, which uses electrical currents to make holes in the cancer cells and destroy them.

Embolization lessens or blocks the flow of blood to liver cancer cells, so that they cannot survive. There are two kinds of embolization:

- Transarterial embolization or chemoembolization is a procedure by which particles meant to cause an obstruction, or those particles plus a high dose of chemotherapy, are injected through a catheter directly into the hepatic artery, the blood vessel that feeds the liver cancer tumor. This strategy is commonly used to treat patients whose liver tumor(s) cannot be removed surgically. It is also increasingly used in many cancer centers, says El-Rayes, as a “bridge to transplant,” meaning it can often either shrink liver cancer tumors or keep them from growing until a liver is available for transplant.

- Radioembolization is a procedure by which small radioactive beads are injected through a catheter into the hepatic artery, through which they travel to reach the liver.

Side effects of embolization for liver cancer can include fever, abdominal pain, nausea, an inflamed gallbladder, liver infection and blood clots.

TARGETED THERAPIES

Nexavar (sorafenib) is the only FDA-approved targeted drug for those with liver cancer; it’s indicated for patients with hepatocellular carcinoma for whom surgery is not an option. Nexavar works by blocking signals that tell cancer cells to grow, while also helping to prevent tumors from forming the new blood vessels that feed them.

Side effects can include, but are not limited to, skin problems, stomach upset, hair loss or thinning, dry mouth, diarrhea and fatigue.

For patients who are resistant to Nexavar, or for whom it is not an option, several targeted drugs are being explored in clinical trials.

“The clinical trials of today are testing the drugs that will become standards of care in 10 years, so it’s important for patients to consider clinical trials,” El-Rayes says.

ON THE HORIZON

Among the most promising targeted therapies in clinical trials, says Abou-Alfa, is cabozantinib, a drug that is already approved to treat thyroid and kidney cancers. Cabozantinib is under investigation in a phase 3 clinical trial, called CELESTIAL, for patients with advanced hepatocellular carcinoma who have already received Nexavar. A MET inhibitor, it works by blocking proteins that encourage the cancer to grow. Like Nexavar, it also stops tumors from growing blood vessels.

Abou-Alfa says he is also “very encouraged” by data on Stivarga (regorafenib), “a cousin to Nexavar,” and on the MET inhibitor tivantinib. In January, the U.S. Food and Drug Administration granted a priority review to Stivarga as a treatment for liver cancer, and expects to make a decision about whether to approve the drug by this summer.

While there is much enthusiasm about new targeted therapies, it is unclear how much these will extend remission times or improve survival until larger-scale trials are carried out. In addition, it is hoped that tissue or blood testing might personalize therapy and be able to match the right drug to the right situation.

Another area of “great interest,” says Abou-Alfa, is immunotherapy, which capitalizes on the body’s immune system — its natural defense system — to fight cancer.

However, he notes that immunotherapy’s full range of “side effects are unknown and should not be underestimated, especially given that liver cancer patients so often have hepatitis or cirrhosis.”

The known side effects can include cough, fatigue, nausea and skin problems. In rare cases, the boosted immune system can attack healthy organs in the body, and that can lead to serious complications.

Mark Yarchoan, M.D., an oncologist at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, says a class of immunotherapeutic drugs called checkpoint inhibitors is “highly promising” for the treatment of liver cancer. These drugs, which inhibit proteins that would otherwise hold the immune system in check, are already approved for several cancers, including lung cancer, melanoma, kidney cancer and head and neck cancers.

Data from the CheckMate-040 study, a phase 3 clinical trial of the checkpoint inhibitor Opdivo (nivolumab) in patients with liver cancer, showed that “one in five patients had measurable tumor shrinkage with Opdivo, while many other patients got their disease to remain stable for sometimes a long time,” Yarchoan says. The results were “so positive,” he says, that “many in the field are hopeful that Opdivo will be better than any treatment that came before it for liver cancer.”

In addition, Abou-Alfa noted that Keytruda (pembrolizumab) and the experimental immunotherapies durvalumab and tremelimumab have “shown promise, but are being studied in clinical trials as well.”

In the future, Yarchoan says, there will likely be trials that combine targeted therapies and immunotherapies for the treatment of liver cancer, as there are for other cancers. “Different drugs destroy cancer cells in different ways,” Yarchoan says. “Using a combination of drugs can increase the chance more cancer cells will be destroyed. Many times, one drug will even help the other drug work better.”