BOSTON, MA – Initial results of the NRG Oncology NRG-GI003 clinical study comparing proton and photon therapy for patients with advanced hepatocellular carcinoma (HCC) indicate that proton therapy did not improve the primary objective of overall survival (OS) for patients. At the planned interim analysis, the trial was released for reporting as the futility boundary was crossed. In addition to overall survival, proton therapy did not improve any of the secondary endpoints of this trial including progression free survival (PFS) and local progression (LP). Although fewer grade 3 or higher treatment-related adverse events were observed with proton therapy compared with photon therapy (11% vs. 24%), this difference was not statistically significant at alpha=0.05 (p=0.093). These results were presented during the Plenary Session of the 2026 American Society for Radiation Oncology Annual Meeting in Boston, Massachusetts.
“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. 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,” stated Theodore S. Hong, MD, from the Dana-Farber Cancer Center at Harvard and the lead author of the NRG-GI003 manuscript.
This Phase III trial accrued 115 eligible patients and stratified them by planned number of treatment fractions (5 or 15 fractions) and presence of tumor vascular thrombosis. Following stratification, patients were randomly assigned to receive either proton therapy or photon therapy given in 5 fractions at 30-50 Gy or 15 fractions at 37.5-67.5 Gy and trial was designed for an overall survival hazard ratio (HR protons/photons ) of 0.58 favoring protons. At the planned interim analysis with 53 events, the trial crossed the futility boundary of HR>1. Median (min-max) follow-up was 20 months (0.13-81.7) for all patients. Protons did not show an improvement in OS compared to photons (1-sided p=0.83, HR=1.30, 90% CI 0.83-2.04). Univariate 24-month OS (90% CIs) was 56.2% (43.9-68.4) for protons and 69.3% (57.3-81.2) for photons. Protons did not show an improvement in PFS (2-sided p=0.92, HR=1.02, 95% CI 0.65-1.62). The 24-month PFS (95% CIs) was 31.6% (17.8-45.4) for protons and 30.4% (15.9-44.8) for photons. Protons did not show a significant improvement in LP (2-sided p=0.54, HR=0.80, 95% CI 0.36-1.77). Notably, the 24-month rates of local progression were relatively low in both treatment arms, at 19.8% with proton therapy and 22.3% with photon therapy. These results are encouraging given the advanced disease population and add to the growing body of evidence suggesting that HCC should not be considered a radioresistant cancer. Overall survival at 24 months was also encouraging in both treatment groups, with rates of 56.2% for patients receiving proton therapy and 69.3% for those receiving photon therapy. Treatment-related grade 3+ AEs were lower for the protons arm, but not significantly different (protons 11%, photons 24%; p=0.09).
This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), UG1CA189867 (NCORP), U24CA180803 (IROC) from the National Cancer Institute (NCI), part of National Institutes of Health. The study is led by NRG Oncology, and conducted by the NIH-funded NCI National Clinical Trials Network (NCTN). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Citations
Hong TS, Winter K, Koay EJ, Kilcoyne A, Franses J, Wolfgang J, Sohn JW, Kachnic LA, Duda DG, Wo JY, Roberts HJ, Ludmir EB, Noticewala S, Kharofa JR, Molitoris JK, Patel PR, Thompson AB, Kabarriti R, Pitter KL, Crane CH. Initial Results of NRG Oncology NRG-GI003: A Phase III Randomized Trial of Protons versus Photons for Hepatocellular Carcinoma (HCC). Paper presented during the Plenary Session at the annual meeting of the American Society for Radiation Oncology. Boston, MA. (2026, September).
About NRG Oncology
NRG Oncology conducts practice-changing, multi-institutional clinical and translational research to improve the lives of patients with cancer. Founded in 2012, NRG Oncology is a Pennsylvania-based nonprofit corporation that integrates the research of the legacy National Surgical Adjuvant Breast and Bowel Project (NSABP), Radiation Therapy Oncology Group (RTOG), and Gynecologic Oncology Group (GOG) programs. The research network seeks to carry out clinical trials with emphasis on sex-specific malignancies, including gynecologic, breast, and prostate cancers, and on localized or locally advanced cancers of all types. NRG Oncology’s extensive research organization comprises multidisciplinary investigators, including medical oncologists, radiation oncologists, surgeons, physicists, pathologists, and statisticians, and encompasses more than 1,300 research sites located world-wide with predominance in the United States and Canada. NRG Oncology is supported primarily through grants from the National Cancer Institute (NCI) and is one of five research groups in the NCI’s National Clinical Trials Network. www.nrgoncology.org