Proton Therapy Does Not Improve Survival in Advanced HCC Trial

Proton therapy did not improve overall survival (OS) compared with photon therapy in patients with advanced hepatocellular carcinoma (HCC), according to initial results from the phase 3 NRG-GI003 trial (NCT03186898).¹

The findings were presented during the plenary session of the 2026 American Society for Radiation Oncology (ASTRO) Annual Meeting in Boston, Massachusetts. The trial crossed its prespecified futility boundary at the planned interim analysis, indicating that proton therapy was unlikely to achieve the anticipated survival benefit over photon therapy.

At the interim analysis, which included 53 events, proton therapy did not improve OS compared with photon therapy (HR, 1.30; 90% CI, 0.83-2.04; 1-sided P =.83). The median follow-up was 20 months, with a range of 0.13 to 81.7 months. The 24-month OS rate was 56.2% (90% CI, 43.9%-68.4%) with proton therapy and 69.3% (90% CI, 57.3%-81.2%) with photon therapy.

“Although these findings were not positive, NRG-GI003 will help us shape the future of research surrounding this disease. 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,” Theodore S. Hong, MD, of Dana-Farber Cancer Center, stated in a news release. “Additionally, outside of survival benefit, future studies should aim to determine whether protons improve quality of life or reduce [adverse] effects when compared to traditional photon therapy.”

About Proton Therapy

Proton therapy is a form of external beam radiation therapy that uses protons rather than photons to deliver radiation to tumors. Unlike conventional photon therapy, in which radiation continues beyond the target as it exits the body, proton therapy can be planned to deposit most of its radiation dose within the tumor and limit radiation exposure to surrounding tissue.

This ability to more precisely concentrate radiation has generated interest in proton therapy for cancers in which sparing nearby healthy organs is particularly important. In HCC, proton therapy may help limit radiation exposure to uninvolved portions of the liver and other surrounding structures, potentially reducing treatment-related toxicity while allowing radiation to be delivered to the tumor.

NRG-GI003 Trial Design

NRG-GI003 was a phase 3 randomized trial designed to determine whether the potential dosimetric advantages of proton therapy could translate into improved clinical outcomes compared with photon therapy in patients with advanced HCC. The trial enrolled 115 eligible patients with advanced HCC.² Patients were stratified according to the planned number of radiation treatment fractions (5 or 15) and the presence of tumor vascular thrombosis before being randomly assigned to proton therapy or photon therapy.

For patients receiving 5 fractions, the prescribed radiation dose ranged from 30 to 50 Gy. For those receiving 15 fractions, the dose ranged from 37.5 to 67.5 Gy. The trial was designed to detect an OS hazard ratio of 0.58 for proton therapy compared with photon therapy, favoring proton treatment.

Additional Findings

The study also found no significant differences in progression-free survival (PFS) or local progression (LP). For PFS, the hazard ratio was 1.02 (95% CI, 0.65-1.62; 2-sided P =.92). The 24-month PFS rate was 31.6% (95% CI, 17.8%-45.4%) in the proton therapy arm and 30.4% (95% CI, 15.9%-44.8%) in the photon therapy arm.

The difference in LP was also not statistically significant (HR, 0.80; 95% CI, 0.36-1.77; 2-sided P =.54). At 24 months, the LP rates were 19.8% with proton therapy and 22.3% with photon therapy.

Regarding safety, grade 3 or higher treatment-related adverse events (AEs) were numerically less frequent with proton therapy. The rates were 11% and 24%, respectively; however, this difference did not reach statistical significance (P =.093).

REFERENCES

1. NRG Oncology Trial Results Show No Survival Benefit with the Use of Proton Therapy for Patients with Advanced Hepatocellular Carcinoma. News release. NRG Oncology. September 28, 2026. Accessed September 29, 2026. https://tinyurl.com/3fscdvr7

2. Radiation Therapy With Protons or Photons in Treating Patients With Liver Cancer. ClinicalTrials.gov. Updated July 2, 2026. Accessed September 29, 2026. https://clinicaltrials.gov/study/NCT03186898