TL;DR
In the randomized NRG-GI003 trial, proton therapy did not improve overall survival over photon radiation for locally advanced liver cancer. Median survival was 26.6 months with protons and 54.9 months with photons, while progression-free survival and local progression rates were similar. Researchers say the results leave open which patients, if any, may benefit more from proton treatment.
A randomized trial of radiation for locally advanced hepatocellular carcinoma found no survival advantage for proton therapy over photon radiation, with patients assigned to photons living a median 54.9 months compared with 26.6 months for those assigned to protons. The NRG-GI003 results, presented at the American Society for Radiation Oncology meeting in Boston, challenge the expectation that protons’ ability to spare healthy liver tissue would improve survival.
The analysis covered 115 randomized patients with measurable disease and up to three liver lesions. More than 90% had Child-Turcotte-Pugh class A liver function, 79% had a single tumor, and 59% received radiation in 15 fractions. Patients could receive treatment in five or 15 fractions, and several prior treatments, including chemotherapy, surgery, chemoembolization and ablation, were allowed.
After a median follow-up of 20.4 months, an interim analysis found a hazard ratio of 1.3 for overall survival, with a 95% confidence interval of 0.83 to 2.04. The result met the trial’s futility threshold. Median progression-free survival was 16.9 months in the proton group and 13.7 months in the photon group; the difference was not statistically significant. Local progression rates and the first site of treatment failure also did not differ significantly.
A subgroup analysis found a treatment interaction involving tumor size: photon therapy performed better among patients with tumors 5 centimeters or larger. The report said the analysis did not show a convincing effect across most other subgroups. Because the tumor-size finding came from a subgroup analysis, it needs further study before it can guide treatment decisions.
Radiation Choices for Advanced Liver Cancer
The findings matter because proton therapy was expected to help by limiting radiation exposure to healthy liver tissue, potentially allowing treatment while preserving more liver function. In this trial, that dosimetric advantage did not translate into longer overall survival. The results also showed similar progression outcomes for the two methods, while severe treatment-related adverse events were numerically less frequent with protons: 11% versus 24% with photons. That difference was not statistically significant (P=0.093).
For clinicians and patients, the study adds evidence to decisions about which radiation method to use, but it does not establish that one approach is preferable for every patient. The strong photon result and the tumor-size signal raise questions about how tumor burden, liver function and treatment planning affect outcomes. The trial’s discussants also argued that radiation could have a role for some patients who might otherwise be considered for other liver-directed therapies.
Why Researchers Expected Proton Benefit
Proton therapy can deposit radiation in a way that reduces exposure beyond the target, while photon radiation is a widely used alternative. Investigators hypothesized that sparing uninvolved liver could improve survival for people with advanced liver cancer. The trial was designed around an ambitious expected benefit: a median overall survival improvement from 14 months with photons to 24 months with protons.
The study followed NRG-RTOG 1112, which established stereotactic body radiation therapy as a standard option for locally advanced hepatocellular carcinoma, according to trial presenter Theodore Hong of Dana-Farber Cancer Institute. Hong said modern systemic treatments, including immune checkpoint combinations, may have contributed to photon outcomes that exceeded the trial’s assumptions. The trial’s “isotoxic” design set radiation doses according to limits on normal liver exposure.
“Ultimately, this trial shows that modern liver radiation, whether using photons or protons, is effective and safe.”
— Erqi Pollom, MD, of Stanford Medicine, an ASTRO discussant
Who May Benefit From Protons
The study does not explain why median survival favored photons or establish whether the tumor-size interaction reflects a reliable difference between treatments. Hong said tumor burden, liver reserve or other factors might help identify patients more likely to benefit from protons, but said further work is needed. The subgroup finding is not enough on its own to establish a treatment rule.
Pollom noted that only 58% of patients assigned to proton therapy received the highest dose level. She said the trial’s local progression rates at two years were about 20% in both groups, which she described as inferior to published proton-therapy results. The reasons for that difference and whether higher proton doses could change outcomes remain unsettled.
Further Study of Dose and Patient Selection
Researchers have not identified a next trial or a timetable for additional results in the report. The questions raised at the ASTRO meeting include whether higher proton doses can be delivered safely and whether tumor size, liver function or other patient characteristics can identify groups more likely to benefit. Until those questions are tested, the trial’s results describe the outcomes of the studied population and treatment design; they do not resolve proton therapy’s role across liver cancer care.
Key Questions
Did proton therapy improve survival in NRG-GI003?
No overall-survival advantage was found. Median survival was 26.6 months with protons and 54.9 months with photons.
Were progression-free survival results different?
Median progression-free survival was 16.9 months with protons and 13.7 months with photons, with no statistically significant difference reported. Local progression rates also did not differ significantly.
Did proton therapy cause fewer severe side effects?
Grade 3 or higher treatment-related adverse events occurred in 11% of the proton group and 24% of the photon group. The reported difference was not statistically significant.
What did the tumor-size analysis find?
The subgroup analysis suggested photon therapy performed better for tumors 5 centimeters or larger. Researchers said more work is needed to determine whether this interaction can guide treatment selection.
Source: rss
