Molecular Profiling Refines Prognosis and Treatment Selection in Low-Grade Glioma

Clinical Summary: 

• Design/Population: The randomized phase 3 EORTC 22033-26033 trial compared upfront radiotherapy with dose-dense temozolomide in 478 patients with clinically high-risk WHO grade 2 low-grade glioma. Long-term outcomes were analyzed after molecular reclassification according to the 2021 WHO criteria.
• Key Outcomes: Initial treatment with radiotherapy or temozolomide resulted in comparable progression-free and overall survival. Molecular classification provided greater prognostic value than clinical risk factors, while age alone was not independently associated with poorer outcomes.
• Clinical Relevance: These findings reinforce the importance of molecular profiling to guide individualized treatment strategies in low-grade glioma as newer targeted therapies continue to emerge.

Brigitta Baumert, MD, PhD, Haaglanden Medical Center, The Hague, Netherlands, discusses long-term findings from the phase 3 EORTC 22033-26033 trial comparing upfront radiotherapy with dose-dense temozolomide in patients with clinically high-risk low-grade glioma.

After extended follow-up, no significant differences in progression-free or overall survival were observed between the treatment arms. Dr Baumert also reviews post hoc molecular analyses demonstrating that molecular subtype is a stronger predictor of long-term outcomes than treatment sequence or age alone, supporting increasingly individualized treatment strategies for patients with low-grade glioma.

Transcript: 

Hello, my name is Brigitta Baumert, and I am a radiation oncologist. I specialize in treating brain tumors and in neuroradiotherapy, I've been doing this now for more than 30 years. Currently, I'm working in the Netherlands at Haaglanden Medical Center. 

Today, I would like to present the long-term results and outcomes of the EORTC 22033-26033 trial which was an intercontinental trial between Europe, the NCI, Canada, Australia, and the UK. 

We randomized 478 patients between first treatment with radiotherapy alone, which was the standard arm, giving 50.4 Gy against the primary treatment with chemotherapy using dose-dense temozolomide for 1 year. The first end point was progression-free survival, which we had already published. There was no difference between the treatment arms. Now we present the long-term overall survival after a median follow-up of 13 years. Again, the same result: there was no difference between the treatment arms in progression-free survival and overall survival.

This trial ran quite long, we started in the early 2000s, accrued patients between 2005 and 2012, and we now have this long-term follow-up. In the meantime, during this trial run, the molecular biology defining low-grade glioma was developed, and we had not integrated the new molecular biology characteristics. However, this was the first trial where we could prospectively stratify for molecular characteristics and we did stratify for 1p status. What we could do was perform a post hoc analysis of the molecular biology for more than 70% of the patients, which is the largest prospective randomized database so far that we have. There, we also found no difference between the treatment groups.

In the meantime, the data from the RTOG trial with combined radiochemotherapy were published, which is still the standard treatment. However, our trial confirmed that there is no difference between both treatments, radiotherapy and chemotherapy. Both treatments also worked at recurrence. We had a 70% crossover of patients, and there was still a response. So you could say we can start with chemotherapy and postpone radiotherapy, but you could also do it the other way around. Standard treatment is still the combined treatment. 

So what does our trial now contribute? What is interesting is molecular biology. We confirmed the molecular subgroups of diffuse astrocytoma and oligodendroglioma that have been defined over the last 2 decades. We had a very small third group of IDH-wild-type gliomas. For those, we cannot really say very much because this is a mixed group. For the IDH-mutant oligodendrogliomas, we did not reach the median overall survival. For the astrocytomas, we reached the median overall survival. However, there was no difference between the treatment arms. This confirms that biology is prognostic and that the treatment sequence as such is not important. That means that, for the future, we will need to base our treatment choices more and more on individualized molecular subgrouping. The first trials have already started using vorasidenib for IDH-mutant glioma. This was one of the major results we could present here: Individualized and tailored treatment for the future will be the main thing. 

Another finding was that the risk factor of age 40 years is no longer valid for patients carrying a low-grade IDH-mutant glioma. We used this clinical factor as a stratification factor, and we could not prove that it has a prognostic impact. This will, however, need to be confirmed in independent databases. 

What are the future ideas? We could not prove that we could postpone radiotherapy with chemotherapy alone. Our original idea was whether we could postpone radiotherapy, or even omit it, to avoid long-term neurotoxic side effects. This will be looked at further, but we did not have enough data here to prove that. This trial took a long time because this is a patient group with high-risk, low-grade glioma who live long. This is a very slowly proliferating tumor, so you need a long follow-up. The other thing is that we fear long-term toxicity because these are mainly younger patients. 

Source: 

Baumert BG, Hegi ME, van den Bent MJ, et al. Temozolomide versus radiotherapy as first-line therapy for low-grade glioma: Mature results of a randomized phase III trial (EORTC 22033-26033/NCIC-CTG/TROG/MRC-CTU). J Clin Oncol. Published online: July 2, 2026. doi: 10.1200/JCO-25-02735