Proton Therapy Doesn't Extend Survival in Advanced Liver Cancer

Proton therapy did not help people with advanced hepatocellular carcinoma (HCC), a type of liver cancer, live longer than standard photon radiation therapy, according to initial results from the phase 3 NRG-GI003 trial.

The findings were presented Sept. 28 during the plenary session of the 2026 American Society for Radiation Oncology (ASTRO) Annual Meeting in Boston. The trial was released for reporting early. At a planned interim analysis, the results crossed a prespecified futility boundary, meaning proton therapy was unlikely to show a survival benefit if the trial continued.

Proton therapy is a type of radiation that can deliver less radiation to healthy liver tissue around a tumor than photon therapy, the more traditional form of radiation. Researchers hoped this would protect liver function and help people live longer.

"The rationale for the study was straightforward: proton therapy can reduce radiation dose to the uninvolved liver compared with photons," said Dr. Theodore S. Hong, lead and presenting author of the study, during his presentation. "Because these patients frequently have compromised underlying liver function, we hypothesized that reducing dose to the normal liver could reduce hepatic decompensation and ultimately improve survival."

Dr. Hong is vice chair of Integration and Collaboration in Radiation Oncology at Beth Israel Deaconess Medical Center and Dana-Farber Cancer Institute and a professor of radiation oncology at Harvard Medical School.

How long did people live with proton versus photon therapy?

The median overall survival was 26.6 months for people who received proton therapy and 54.9 months for those who received photon therapy. Overall survival is the length of time people lived after starting treatment.

Dr. Hong noted that the proton therapy group lived about as long as researchers expected. The photon therapy group, however, lived far longer than the 14 months assumed when the trial was designed.

"There was no survival benefit with proton therapy," Dr. Hong said. "Note that the proton arm actually performed similarly to the 24-month median survival projected in the study. However, the photon arm, where the median survival was nearly 55 months, dramatically exceeded the 14 months assumed in the original statistical design."

Proton therapy also did not improve progression-free survival, which is the time people lived without their cancer growing or spreading. The median progression-free survival was 16.9 months with proton therapy and 13.7 months with photon therapy, a difference that was not statistically significant.

Proton therapy also did not reduce the chance of cancer growing back in the treated area. At 24 months, this had happened in 19.8% of people who received proton therapy and 22.3% of those who received photon therapy.

Did tumor size make a difference?

When researchers looked back at subgroups of people in the trial, tumor size appeared to affect how people did with each treatment. For people with tumors smaller than 5 centimeters, 66.9% of those treated with photons and 66% of those treated with protons were alive at 24 months, and outcomes numerically favored protons. For people with tumors 5 centimeters or larger, 73.7% of those treated with photons were alive at 24 months, compared with 47.5% of those treated with protons.

Dr. Hong cautioned that this analysis was done after the trial ended and was not designed to answer this question.

"Please remember this is a post hoc analysis, and this should be considered hypothesis generating rather than definitive," he said.

He added in a press release from NRG Oncology that the findings will help guide future research.

"The data from this trial shifts our focus to identifying potential subgroups of patients with HCC who may be more likely to derive benefit from proton therapy," Dr. Hong said. "Additionally, outside of survival benefit, future studies should aim to determine whether protons improve quality of life or reduce [side effects] when compared to traditional photon therapy."

Who was included in the NRG-GI003 trial?

The trial included people with HCC that could not be removed with surgery or that had come back in the liver. Participants had up to three tumors, relatively preserved liver function and good overall physical functioning. People who had previously received other cancer treatments were allowed to enroll.

Participants were randomly assigned to receive either proton or photon radiation therapy. Radiation was given in either five or 15 treatment sessions, with doses tailored to each person.

Between June 2017 and January 2026, 116 people were randomly assigned to a treatment group, and 115 were included in the analysis: 57 received proton therapy and 58 received photon therapy. The trial originally planned to enroll 167 people, but enrollment was slower than expected, and the target was lowered to 118.

The median age of participants was 72 years. Most (79%) had a single tumor, and the median tumor size was 5.1 centimeters. In 25% of participants, the tumor had grown into nearby blood vessels.

What side effects did people experience with proton therapy?

Severe (grade 3 or higher) treatment-related side effects occurred in 11% of people who received proton therapy and 24% of those who received photon therapy. The difference was not statistically significant, so it may have been due to chance. The most common severe side effect was a drop in lymphocytes, a type of white blood cell. It was recorded in 9% of people in the proton group and 22% in the photon group. No one in either group died from treatment-related side effects.

The trial confirmed that proton therapy delivered less radiation to healthy liver tissue. For people who received five treatment sessions, the median dose to the healthy liver was 8.5 Gy with protons versus 12.8 Gy with photons. For those who received 15 sessions, it was 12.7 Gy versus 20.3 Gy. Gy, or gray, is the unit used to measure radiation dose.

"This slide demonstrates that the fundamental dosimetric premise of the trial was correct: protons substantially reduced the mean dose to the uninvolved liver," Dr. Hong said. "There was also a numerical reduction in grade 3 or higher treatment-related [side effects]... although this did not reach conventional statistical significance. Overall, severe toxicity was uncommon in both groups, and there were no grade 5 treatment-related events."

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