ONLY ABOUT 30% of people diagnosed with hepatocellular carcinoma (HCC), the most common type of liver cancer in the U.S., are considered candidates for surgery. That occurs partly because liver cancer is often diagnosed at later stages. But even when the cancer is discovered before it has spread to other parts of the body, factors such as the size of the mass, the presence of multiple tumors, and tumor infiltration into large blood vessels in the kidney can put surgery out of reach for those with early-stage disease.

However, with the approval of several immune checkpoint inhibitors (ICIs) in advanced HCC over the last decade, researchers are exploring whether immunotherapy before surgery, also called neoadjuvant immunotherapy, might be used in people who have early-stage liver cancer to help make them eligible for surgery and to increase recurrence-free survival.

A study published Aug. 15, 2024, in Cancer Research Communications looked at data from 92 people with early-stage HCC who underwent surgery at the Johns Hopkins Kimmel Cancer Center in Baltimore from 2017 to 2023. Among those patients, 36 people received immunotherapy before surgery. Those who received immunotherapy prior to surgery had a median recurrence-free survival of 44.8 months, compared with 49.3 months for those who had surgery without immunotherapy.

Although this difference is small and not statistically significant in the study, those who received immunotherapy prior to surgery also had features of a more aggressive cancer. In fact, 22 of the 36 people who received immunotherapy prior to surgery did not meet traditional eligibility criteria for surgery, including having larger tumors and more vascular involvement, which made recurrence more likely. But almost all the patients who had immunotherapy had successful surgery, which means the cancer was safely removed even in this high-risk population.

“Those patients have outcomes that are essentially equivalent to the lower-risk patients who get upfront surgery,” says Mark Yarchoan, senior author of the study and a medical oncologist at the Johns Hopkins Kimmel Cancer Center. The researchers could examine these data from high-risk patients because Johns Hopkins offers immunotherapy prior to surgery as part of its research even when people with early-stage disease might traditionally be ineligible for surgery.

These findings suggest neoadjuvant immunotherapy can help improve outcomes for those with high-risk disease, but Yarchoan says he is eager to see a clinical trial that looks at neoadjuvant therapy and surgery compared with surgery alone to determine whether immunotherapy delivered before surgery could extend remissions in appropriate populations. “We really need to study this prospectively with a randomized clinical trial to be absolutely sure that this is correct, but [this study] does provide initial evidence that immunotherapy before surgery can essentially negate some of the risk of very high-risk HCCs,” says Yarchoan.

This study looked at several ICIs, including Opdivo (nivolumab) alone and in combination with other ICIs and targeted therapies, but did not compare outcomes associated with different ICIs. In theory, immunotherapy delivered before surgery could potentially lead to better outcomes since cancer cells in the body can help ICIs, which take the brakes off the immune system, create an even stronger immune response to the cancer that is present in the body.

“When the tumor is still present, it has multiple antigens that the immune system can react to. Then you might have a more robust response,” explains Kelley Coffman D’Annibale, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City who was not involved in the study. D’Annibale says she is also curious how people with early-stage liver cancer who are not candidates for surgery would do if they just received immunotherapy.

ICIs are currently approved by the Food and Drug Administration for advanced-stage HCC, including as a first-line treatment and as a second-line treatment after other therapies have failed.