A targeted radiation boost delivered during surgery did not improve progression-free survival or overall survival for patients with newly diagnosed, resectable glioblastoma in the phase 3 INTRAGO-II trial.
The international randomized study evaluated whether adding low-kilovoltage intraoperative radiotherapy to maximal safe resection and standard postoperative chemoradiotherapy could improve outcomes in a disease where local recurrence remains the dominant pattern of failure.
Despite the ability to deliver a high radiation dose directly to the resection cavity, the approach did not change survival outcomes or reduce local recurrence.
A Longstanding Challenge in Glioblastoma Care
Glioblastoma remains the most aggressive primary malignant brain tumour in adults. Even after maximal safe resection followed by radiotherapy and temozolomide, most tumours recur, often close to the original surgical cavity.
This pattern has led researchers to explore whether more intensive local treatment could improve disease control. Strategies have included wider surgical resection, brachytherapy, stereotactic radiosurgery, and dose-escalated external-beam radiotherapy.
Intraoperative radiotherapy was considered a technically appealing option because it allows radiation to be delivered immediately after tumour removal, directly to the margins of the resection cavity. The technique uses a steep dose gradient, aiming to expose nearby residual tumour cells while limiting radiation to deeper healthy tissue.
Earlier phase 1/2 findings from the INTRAGO-I study suggested that the approach was feasible and could potentially support further investigation.
Testing a 30 Gy Radiation Boost During Surgery
INTRAGO-II was an open-label, multicentre, randomized phase 3 trial conducted across 18 centres in Brazil, Canada, China, Germany, Spain, South Korea, and the United States.
Eligible patients were aged 18–80 years and had newly diagnosed supratentorial glioblastoma that was considered amenable to resection. All participants had a Karnofsky performance score of at least 60%.
Patients were randomly assigned during surgery to receive either:
- maximal safe resection followed by intraoperative radiotherapy and standard postoperative treatment; or
- maximal safe resection followed by standard postoperative treatment alone.
In the intraoperative radiotherapy group, patients received a recommended 30 Gy surface dose using the INTRABEAM system. Dose reductions to 20–25 Gy were permitted when nearby organs at risk could receive excessive radiation exposure.
Both groups received standard chemoradiotherapy after surgery, including external-beam radiotherapy to 60 Gy with concurrent temozolomide, followed by adjuvant temozolomide.
A total of 314 patients were randomly assigned. The final analysis included 298 patients: 161 in the intraoperative radiotherapy group and 137 in the standard-of-care group.
No Improvement in Progression-Free Survival
At a median follow-up of 17.2 months, intraoperative radiotherapy did not improve the primary endpoint of progression-free survival.
Median progression-free survival was 11.0 months in the intraoperative radiotherapy group, compared with 11.4 months in the standard-of-care group.
The hazard ratio was 1.1 (95% CI 0.85–1.44; p=0.47), showing no evidence that the radiation boost delayed progression.
The absence of benefit was consistent across prespecified subgroups, including analyses based on age, sex, Karnofsky performance status, MGMT promoter methylation status, IDH1 mutation status, chemotherapy administration, and residual tumour.
Overall Survival Also Remained Unchanged
The addition of intraoperative radiotherapy did not improve overall survival.
Median overall survival was 17.7 months in the intraoperative radiotherapy group and 18.7 months in the standard-of-care group.
The hazard ratio for overall survival was 1.2 (95% CI 0.91–1.54; p=0.20).
These findings indicate that immediate local dose escalation at the surgical cavity did not translate into a survival advantage when added to current postoperative chemoradiotherapy.
Local Recurrence Continued to Dominate
Local recurrence remained the most common pattern of disease progression in both study groups.
Among patients assessed through centralized review, local recurrence within 1 cm of the resection cavity occurred in 72% of patients receiving intraoperative radiotherapy and 71% of patients receiving standard treatment alone.
There was no significant difference between groups.
The finding is particularly important because the treatment was designed specifically to improve local control. Even with the additional radiation boost, glioblastoma continued to recur predominantly near the original tumour site.
Safety Findings Require Attention
The study reported more serious adverse events among patients receiving intraoperative radiotherapy.
Serious adverse events occurred in 65% of patients in the intraoperative radiotherapy group, compared with 53% in the standard-of-care group.
Grade 3–4 seizures occurred in 13% of patients receiving intraoperative radiotherapy and 7% of those receiving standard treatment. Radiation necrosis was reported in 7% and 2% of patients, respectively.
Wound complications were also more frequent in the intraoperative radiotherapy group, although wound-related events were grade 3 or lower.
The authors noted that the study was not designed to establish whether every difference in adverse events was directly caused by intraoperative radiotherapy. However, the safety findings add to the importance of assessing the balance between treatment burden and clinical benefit.
What the Results Mean for Local Dose Escalation
The INTRAGO-II results challenge the value of further local radiation dose intensification in resectable glioblastoma.
The investigators pointed to a central biological and geometric problem: glioblastoma cells can infiltrate brain tissue several centimetres beyond the visible contrast-enhancing tumour margin, while the effect of intraoperative radiotherapy falls sharply with increasing distance from the surgical cavity.
Although the prescribed dose was 30 Gy at the cavity surface, the dose decreases substantially within a few millimetres. This may leave infiltrating tumour cells beyond the high-dose zone relatively unaffected.
The lack of benefit also raises questions about whether residual glioblastoma cells may be more resistant to radiation than previously recognized, or whether the local tumour microenvironment plays a larger role in recurrence than can be addressed through cavity-directed radiation alone.
A Clear Result From a Large Randomized Trial
INTRAGO-II is one of the largest randomized trials to directly test intraoperative radiotherapy in newly diagnosed glioblastoma.
Its findings show that adding a 30 Gy low-kilovoltage intraoperative radiotherapy boost to surgery and standard chemoradiotherapy did not improve progression-free survival, overall survival, or local recurrence patterns.
For patients with resectable glioblastoma, the study suggests that further gains are unlikely to come from local radiation dose escalation alone and that new strategies will be needed to address the infiltrative biology of the disease.
Written by Nare Hovhannisyan, MD
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