MRI-Guided Adaptive Radiotherapy Safely Reduces Treatment Margins in Glioblastoma

Clinical Summary: 

• Design/Population: The phase 2 UNITED trial evaluated MRI-guided adaptive radiotherapy with reduced treatment margins in adult patients with newly diagnosed IDH-wildtype glioblastoma receiving standard chemoradiotherapy using a 1.5-T MRI-linear accelerator.
• Key Outcomes: MRI-guided adaptive radiotherapy achieved a low rate of marginal failure while substantially reducing radiation treatment volumes compared with conventional approaches. Treatment was well tolerated, with manageable toxicity and no treatment-related deaths.
• Clinical Relevance: These findings support MRI-guided adaptive radiotherapy as a safe strategy to reduce radiation exposure to normal brain tissue and provide the foundation for randomized studies evaluating quality-of-life and long-term toxicity outcomes.

Jay Detsky, MD PhD, Odette Cancer Centre, Toronto, Canada, discusses results from the phase 2 UNITED trial evaluating MRI-guided adaptive radiotherapy with reduced treatment margins for patients with newly diagnosed glioblastoma. The study assessed whether daily MRI guidance and adaptive replanning could safely reduce radiation volumes while maintaining tumor control.

The study demonstrated a low rate of marginal failure despite substantially smaller treatment margins than conventional radiotherapy, supporting the safety of MRI-guided adaptive treatment. Dr Detsky also discusses ongoing efforts to launch an international randomized trial comparing this approach with standard radiotherapy to determine whether reducing irradiated brain volume improves long-term toxicity and quality of life.

Transcript: 

Hi, I'm Dr Jay Detsky. I'm a CNS radiation oncologist at the Odette Cancer Centre at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada. I'm the principal investigator of the UNITED study, which is looking at small-margin adaptive radiation for glioblastoma.

For many years, the standard after surgery to remove as much of this type of brain cancer as possible has been either 3 or 6 weeks of radiation, delivered daily over either 15 or 30 fractions, together with a concurrent chemotherapy pill called temozolomide. The standard approach has been to obtain a single MRI and CT scan, design a radiation plan, and then apply a fairly large safety margin. These tumors can shift, grow, shrink, and evolve during treatment.

Traditionally, we have not performed MRI imaging during the 6-week course of radiation, so the standard safety margin has been somewhere between 15 and 30 millimeters. As a result, we end up treating a large portion of the brain surrounding the residual tumor and surgical cavity in order to reduce the chance that the tumor regrows at the edge of the radiation field. Those very large safety margins affect patients because they increase side effects. We're radiating larger areas of the brain, so fatigue can be worse, headaches can be worse, nausea can be worse, and we also know that treating larger areas of the brain can affect lymphocyte counts, or white blood cell counts.

For all of these reasons, we've been trying to find a way to improve radiation delivery by using much smaller safety margins. From previous studies, including work we reported several years ago, we knew that if you simply reduced the safety margin to something like 5 millimeters without imaging during treatment, you could miss tumors because some of these tumors move substantially over the course of radiation. So we wanted to leverage a new technology called the MR-LINAC, which combines an MRI scanner with a linear accelerator for radiation delivery.

The platform we used is called Unity, and that's partly why the study is called the UNITED study. The idea was to use a very small 5-millimeter safety margin while performing MRI every single day—once a week with contrast and the other treatment days without contrast—to track the tumor as it evolved and adapt the radiation plan accordingly. This was the first time this small-margin adaptive approach had been tested in humans. We treated 98 patients, the goal of the study was really to prove the safety of this approach. 

Specifically, we looked at the risk of what we call marginal failure, meaning tumor growing back right at or just outside the edge of the radiation field. The concern from us and our colleagues around the world was that if you reduced the margin so dramatically, you might miss the tumor at the edge. Previous studies using 15- to 30-millimeter margins reported marginal failure rates of approximately 10%. Our statistical design required that, among the 98 treated patients, there be no more than 13 marginal failures to demonstrate that this approach was safe. 

We enrolled those 98 patients between early 2021 and early 2023. All patients received either 3 or 6 weeks of radiation, depending on age and performance status, both of which are standard approaches. Every patient was treated on the Unity MR-LINAC. All patients were treated using a 5-millimeter margin with MR-guided adaptive replanning. We adjusted the radiation plan every day based on the MRI findings and the changes we observed in the tumor and surrounding brain. All patients completed radiation together with concurrent temozolomide chemotherapy. All patients had IDH-wild-type glioblastoma. 

The primary results were published in The Lancet Oncology in May of this year. We found that there were only four marginal failures among the 98 patients. That was well below the threshold of 13 and actually lower than anticipated so, we were reassured that this approach was safe. 

We also compared our treatment volumes with current standards. Compared with the European and Canadian EORTC guidelines, our treatment volumes were approximately 40% smaller. Compared with the larger RTOG approach commonly used in the United States, our treatment volumes were approximately 70% smaller. Overall survival and progression-free survival were in line with historical results. Patients achieved similar survival while receiving substantially less radiation to normal brain tissue, and we observed very few marginal failures.

These findings demonstrate that by tracking tumors with MRI and adapting treatment daily, it is possible to safely reduce treatment margins. This is really the first step in demonstrating the safety of this approach. The next step is a randomized clinical trial.

We're currently designing that study together with colleagues from around the world through the MR-LINAC Consortium. Patients will be randomized to either standard 3- or 6-week radiation with conventional larger margins and no adaptive MRI guidance or the adaptive MR-guided approach used in the UNITED study. We want to demonstrate equivalent survival while also showing improvements in quality of life and treatment tolerability resulting from the substantially smaller treatment volumes.

This work has generated considerable interest from other investigators who are exploring additional approaches to optimize MR-guided adaptive radiation. It is more resource intensive. Instead of a typical 15- to 20-minute radiation appointment, treatment on the MR-LINAC generally takes 30 to 40 minutes, and sometimes as long as an hour. It also requires more involvement from radiation therapists and radiation oncologists because treatment is adapted and replanned every day. However, we believe this additional effort is worthwhile because patients tolerated treatment better than we were accustomed to seeing with larger treatment volumes.

We have also recently updated our long-term outcomes. At the time of publication, follow-up extended to approximately 2 years. We now have 4 to 5 years of follow-up and will be presenting those updated data at an upcoming conference. Among the 98 patients we treated, 12 remain alive, and 5 are alive with no evidence of disease recurrence. Among patients who received 6 weeks of radiation, 22% were alive at three years, which compares favorably with most previously reported studies. For this small group of long-term survivors, reducing the late effects of radiation becomes especially important because radiation-related effects on memory, concentration, thinking, and executive function can be lifelong.

For patients who live 3, 4, or 5 years, minimizing the amount of the normal brain exposed to radiation is particularly meaningful. We believe this adaptive small-margin approach is one of the best ways to accomplish that, and we will continue investigating and refining this strategy to further improve treatment for patients with glioblastoma.

Source: 

Detsky JS, Chan AW, Moore-Palhares D, et al. MRI-guided adaptive radiotherapy for high grade glioma (UNITED): A single-centre, single-arm, non-inferiority, phase 2 trial. Lancet Oncol. Published online: May 14, 2026. doi: 10.1016/s1470-2045(26)00088-4