Glioblastoma has repeatedly taught radiation oncologists an uncomfortable lesson: greater precision and greater radiation intensity do not necessarily translate into better outcomes.
The recently published phase III GOLD trial has reinforced that message. In newly diagnosed glioblastoma, ultra-hypofractionated chemoradiation with 36 Gy in six fractions was compared with conventional 60 Gy in 30 fractions, both with temozolomide. The experimental strategy failed to demonstrate non-inferiority and was associated with worse disease control and greater toxicity, including radiation necrosis.
Yet stereotactic radiation continues to be investigated in GBM. Why?
Perhaps because the question is changing.
We Have Tried Dose Escalation Before
More than two decades ago, RTOG 93-05 tested whether adding an upfront single-fraction stereotactic radiosurgery (SRS) boost to conventional treatment could improve survival.
It did not.
The biological explanation is intuitive. Unlike a brain metastasis, GBM is not simply the contrast-enhancing lesion visible on MRI. Malignant cells infiltrate well beyond conventional imaging boundaries. The problem may therefore never have been our ability to hit the target. It may have been expecting the target to represent the disease.
Interestingly, the six-fraction concept predates GOLD. A phase II study by Omuro and colleagues used 6 × 6 Gy to enhancing disease with 6 × 4 Gy to surrounding FLAIR abnormality, combined with temozolomide and bevacizumab. Median survival reached 19 months.
Encouraging but in a 40-patient single-arm study.
GOLD provides an important reminder of why promising early-phase radiation strategies require randomized validation.
Recurrence May Be Different
The recurrent setting tells a more nuanced story. In NRG/RTOG 1205, patients with recurrentm GBM received bevacizumab with or without focal reirradiation to 35 Gy in 10 fractions.
Overall survival was unchanged. But six-month progression-free survival increased fromm approximately 29% to 54%, and treatment was well tolerated.
That distinction matters.
In GBM, delaying focal neurologic progression may be clinically valuable even when subsequent infiltrative disease ultimately determines survival.
The relevant question at recurrence may therefore not simply be whether stereotactic radiation prolongs life, but whether it can provide meaningful local disease control in appropriately selected patients.
What Treats the Disease Outside the Radiation Field?
Modern studies are beginning to address the central limitation of focal radiation directly.
A Stanford phase I study combined 35 Gy in five fractions with temozolomide and Tumor Treating Fields (TTFields) in newly diagnosed GBM.
The concept is intriguing: stereotactic radiation intensively treats macroscopic disease, while TTFields provides a spatially broader therapy that is not restricted to the radiation volume.
A Johns Hopkins/Stanford phase I trial explored SRS combined with dual TIM-3/PD-1 checkpoint blockade in recurrent GBM.
Here, radiation has a different purpose. Rather than simply escalating dose, high-dose focalradiation is being investigated a biological perturbation capable of altering tumor-cell injury, antigen presentation, and the immune microenvironment.
Whether radiation can meaningfully convert GBM into an immunologically responsive tumor remains unproven. But the conceptual shift is important. Stereotactic radiation becomes a therapeutic partner rather than a standalone solution.
Maybe We Are Treating the Wrong GBMs
Patient selection may be equally important. Recent retrospective Cleveland Clinic data suggestn that outcomes following salvage SRS differ substantially according to tumor volume, time ton recurrence, and potentially molecular characteristics involving chromosome 19q13.
These findings do not establish a predictive biomarker for SRS. Patients with thesen characteristics may simply have more favorable disease biology.
But they raise a more sophisticated question:
Instead of asking “Does SRS work in recurrent GBM?”, should we ask “Which GBM ismbiologically appropriate for SRS?”
From Anatomical to Biological Precision
This may be where the field ultimately needs to go.
GBM is heterogeneous not only spatially but biologically. Different tumor regions may vary in hypoxia, DNA-repair capacity, replication stress, metabolism and immune composition.
Future stereotactic strategies could therefore combine focal radiation with therapies selected according to those vulnerabilities for example, targeting replication stress, DNA repair or immune resistance.
Advanced imaging might similarly identify resistant biological subvolumes rather than relying exclusively on contrast enhancement.
In this model, stereotactic radiation begins to resemble a targeted drug: it has a dose, a spatial distribution, a biological effect and perhaps it should have a biomarker.
What GOLD Really Teaches Us
GOLD should discourage the assumption that fewer, larger fractions are inherently better for newly diagnosed GBM. But it does not mean every form of stereotactic radiation is futile.
The collective evidence instead suggests that the purpose of focal radiation depends on the clinical setting. Upfront dose escalation has repeatedly failed to overcome infiltrative biology.
At recurrence, focal reirradiation can improve disease control in selected patients even without extending overall survival.
Emerging studies are asking whether stereotactic radiation can serve as a partner for therapies acting beyond the radiation field, or as a biological perturbation that enhances another treatment.
These are fundamentally different hypotheses.
The next generation of GBM trials should therefore move beyond asking: How much radiation can we deliver, and in how few fractions?
The more important questions are: Whom should we irradiate? What biological compartment should we target? What are we trying to achieve? And what therapy will address the disease outside the high-dose volume?
Written By Ahmed Galal, MD