Results from the photon cohort of NRG-BN001, a signal seeking Phase II randomized trial, has delivered hope to patients battling glioblastoma, one of the most aggressive brain tumors, suggesting that advanced proton therapy may improve survival without adding significant side effects.
For decades, researchers tried increasing radiation dose for glioblastoma using photons, but “when the larger randomized trials were done, they all tended to be negative,” said Dr. Minesh P. Mehta, the study’s lead investigator. The photon dose-escalation arm of BN001 confirmed the same: raising the dose from 60 to 75 Gy did not produce a survival benefit.
The proton arm told a different story. Patients received 75 Gy using proton therapy over the same six-week schedule. Despite having slightly worse prognostic factors, these patients experienced a 19% reduction in risk of death compared to the standard photon group. The absolute survival advantage was about 7% at two years and 5% at three years.
“These numbers were statistically significant,” Mehta said, noting the trial’s pre-specified statistical threshold for a positive signal. “There’s an 89% probability that the result was not by chance alone.”
The proton arm saw substantially less lymphopenia, a treatment-related loss of white blood cells. Mehta said that protons expose less healthy brain tissue and circulating blood to low-dose radiation, which helps preserve immune function. Severe lymphopenia is linked to infections, poorer cancer control, and reduced survival.
The trial was purposely designed as a “signal-seeking” study because investigators “did not know which hypothesis would be correct.” Even with this early-phase design, Mehta noted that the proton arm performed better despite including more patients with poor predictors of outcome, such as unmethylated MGMT status and fewer complete resections.
Another important finding was that escalating the dose with protons did not produce a major increase in side effects. “Statistically, there was no significant difference in grade three or higher toxicities,” Mehta said. This demonstrated that protons could safely deliver higher doses.
The results, he said, provide “a positive signal” strong enough to justify moving to a definitive phase III trial, which the team is now developing.
Still, Mehta said that 60 Gy photon therapy with temozolomide remains the standard of care, though selected patients with more favorable prognostic factors – such as younger age, MGMT methylation, and near-total tumor resection – can consider proton therapy while the next trial is underway.
“We were seeking a signal,” he said. “We found a signal. Now we take it to the next level.”
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