November 2020 Edition Vol.11, Issue 11

New Clinical Guidance on Treatment for Inoperable Liver Cancer

By Aaron Tallent

Seven of the world’s leading liver cancer specialists have developed clinical guidance calling for physicians to consider different treatment options in treating patients with inoperable hepatocellular carcinoma (HCC). The expert statement is intended to guide physicians and patients in selecting which treatment to apply based on disease stage, tumor characteristics, and liver function.

The standard treatment for HCC since the 1980s has been transcatheter arterial chemoembolization (TACE), where chemotherapy is injected into the hepatic artery and its blood flow is blocked for a short period of time to help kill the tumor cells. However, the results from a number of phase III clinical trials have established more first- and second-line therapies that if effectively sequenced, have the potential to increase survival beyond two years in patients with inoperable HCC.

“We are talking about a common tumor, and a very deadly tumor, but we are fortunate in that we are now having more treatment options than a decade ago,” said Peter Galle, MD, a member of the statement working group and Director of the Department of Internal Medicine at the University Medical Center in Mainz, Germany, on a webinar announcing the release of the statement.

Worldwide, liver cancer is the currently the sixth most common cancer and the fourth most common cause of cancer death, but its incidence is also growing at a rate much faster than most common cancers. Its global incidence has increased by 38% from 2006 to 2016 and is projected to grow by 122% in the United States between 2016 and 2030.

HCC is the most common form of liver cancer in adults, accounting for 75% to 85% of all cases with a five-year survival rate of 14%. The main reason for the poor prognosis is that only 30% of HCC patients are even eligible for curative treatment, such as a liver transplant or resection (surgical removal of the tumor). The rest are diagnosed at an advanced stage where the HCC is unresectable and cannot receive curative treatment.

“To give someone curative therapy, we need [the tumor] at like the size of a golf ball or a small orange, but the liver’s a football and you can hide a lot of things in there without feeling it or seeing lab changes,” said Catherine Frenette, MD, a statement working group member and Medical Director of the Liver Transplantation Program at Scripps Green Hospital in San Diego. “Many patients will have no symptoms at early stage disease, and they don’t develop symptoms until it is very advanced.’

In approximately 90% of HCC cases, the tumor begins to develop after the patient has suffered chronic liver disease and liver cirrhosis. There are many causes for both, including the hepatitis B virus, alcohol consumption, obesity, tobacco smoking, and non-alcoholic fatty liver disease (NALFD). The incidence of NALFD-related HCC has increased with the overall rise of the disease.

“Liver cancer is a complicated disease,” said Richard Finn, MD, a statement working group member and Professor of Medicine at the Geffen School of Medicine at UCLA in the Department of Medicine, Division of Hematology/Oncology. “Unlike a lot of malignancies we treat, it is really two diseases. It’s chronic liver disease and it’s an underlying malignancy.”

In the past 15 years, the Food and Drug Administration (FDA) has approved three front-line systemic treatments for unresectable HCC: sorafenib, lenvatinib, and atezolizumab + bevacizumab. In addition, positive clinical trial results have also yielded a number of second-line therapies, including: regorafenib, cabozantinib, ramucirumab, nivolumab, pembrolizumab, and nivolumab + ipilimumab (Figure 1). The expert statement provides guidance on applying them after TACE and new recommendations on administering them instead of TACE.

The Barcelona Clinic Liver Cancer (BCLC) system is the most widely used by oncologists for staging HCC and has five stages based on a number of characteristics: very early (BCLC stage 0), early (BCLC stage A), intermediate (BCLC stage B), advanced (BCLC stage C), and terminal (BCLC stage D). Very early and early stage HCC, which is characterized by no more than three nodules and preserved liver function, can be treated with curative therapies.

For immediate stage, which has more nodules, but preserved liver function and no vascular invasion or extrahepatic spread, the recommended treatment has historically been TACE. However, the statement authors warn that intermediate-stage HCC patients are diverse and the BCLC staging system may not fully cover the tumor burden or liver function, which is impaired with each round of TACE. The damage is caused by the fact that the chemotherapy injected through the hepatic artery hits not only the tumor, but a subsegment of the liver as well.

“Every time chemoembolization is done, even though they’re super-selective and try to spare normal liver, we know that patients with cirrhosis have limited reserve,” said Dr. Finn. “Every chemoembolization procedure nibbles at that reserve and to get the optimal benefit from systemic treatment, we need patients to have well-compensated liver function. Once a patient decompensates, it’s hard to recover that liver function and makes it more difficult to treat them with systemic treatment.”

The statement offers guidance on getting the most out of each TACE treatment or forgoing it altogether by drawing distinctions between intermediate-stage HCC patients, whose number and size of nodules can differ by wide margins. The working group assessed that patients with no more than seven nodules that are no larger than six centimeters would likely have a good response to TACE, while those with more or larger nodules would not. For the latter, the recommendation is to explore a systemic therapy. If a patient has advanced-stage HCC, then the recommendation is for he or she to receive a systemic therapy.

“In simple words, those patients with a limited number of nodules and nodules of a limited size are probably, even in the future, good candidates for TACE,” said Prof. Galle. “But those patients where there is a high tumor burden and respective multiple nodules and very huge nodules, they may in fact not be good candidates at all for [TACE] and we know that their response to TACE is poorer.”

Once the treatment is selected, the working group recommends a multidisciplinary treatment approach of three Ps, planning, proactivity, and progression, to effectively treat and manage HCC. The planning comes with choosing the therapy, the proactivity in monitoring the disease, efficacy of the treatment, and liver function, and progression involves assessing the disease and treatment sequencing.

If patients are able to make an effective and timely transition from first-line to second-line systemic therapy, they have the potential to improve their prolonged survival. For example, a retrospective analysis of patients treated in the RESORCE study indicated a survival benefit of 26 months with the treatment sequence of sorafenib followed by regorafenib. However, the only data available on all second-line treatments comes from their sequenced use with sorafenib.

“All of the second-line data was done after sorafenib,” said Dr. Frenette. “There’s a little bit of post-immunotherapy mixed into those trials, but we have to make sure that the patient understands that when we’re thinking about subsequent lines of therapy, we really are in a little bit of a data-free zone right now and we desperately need some data on what is appropriate and has benefit after immunotherapy.”

The one second-line therapy with data on its use in sequence with the immunotherapy treatment atezolizumab is cabozantinib, as the combination is being studied in the COSMIC-312 trial for its efficacy as a potential first-line treatment for advanced HCC. The CELESTIAL trial also produced a small amount of data on the tyrosine kinase inhibitor as a third-line therapy.

“Cabozantinib has been shown to be effective in second-line [treatment],” said Prof. Galle. “It was a population of mostly post-sorafenib [patients], but it is actually interesting to mention roughly a quarter of the population treated was, in fact, in third line.”

Regardless of the therapy, the statement recommends that all aspects of treatment be decided by both the physician and the patient after close consultation between the two. This includes discussing the safety, the quality of life, side effects, the pros and cons of each treatment, and the life the patient wishes to live.

“For someone who is already on three blood pressure medicines, giving them a drug that’s going to worsen their blood pressure may not be the right choice. Whereas, somebody who is a landscaper and still wants to be able to work and he’s really tough on his hands and his feet all day every day, having hand/foot skin reaction may not be best option for him,” said Dr. Frenette.

Now that the statement has been released, the goal of the working group is to share this information with the people who will benefit from it the most. This includes community oncologists, interventional radiologists, surgeons, and, of course, patients.

“What we really want to do is make sure to educate the people that may not do this every day and don’t realize the huge progress we have made with liver cancer,” said Dr. Frenette.

The development of this expert statement was initiated and fully funded by Bayer. The working group gave final editorial approval for the opinions and conclusions contained in this expert statement.

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