December 03, 2025
2 min watch
Key takeaways:
- Patients who received MRI-guided focused ultrasound with chemotherapy survived nearly 40% longer than those who received chemotherapy alone.
- The approach appeared safe, with no treatment-related deaths.
Use of MRI-guided focused ultrasound with standard chemotherapy is safe and may improve outcomes for people with glioblastoma, results of a phase 1/2 trial showed.
Patients treated with this regimen survived nearly 40% longer than those who received chemotherapy alone. No treatment-related deaths occurred, and only one adverse event deemed related to focused ultrasound exceeded grade 2.
Data derived from Woodworth GF, et al. Lancet Oncol. 2025;doi:10.1016/S1470-2045(25)00492-9.
The findings — the first evidence that using focused ultrasound to open the blood-brain barrier during adjuvant chemotherapy delivery may improve survival — support further evaluation of this approach in randomized controlled trials, researchers concluded.
Graeme F. Woodworth
“The fact that this tool can safely deliver and contour ultrasound energy within large, uniquely shaped, heterogeneous brain regions and around structures that historically hinder the ability to target sound waves into the brain is remarkable,” Graeme F. Woodworth, MD, FAANS, FACS, chair of neurosurgery at University of Maryland School of Medicine and director of the brain tumor program at University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, told Healio.
“The survival outcomes are very important and are commonly featured in the headlines,” Woodworth added. “But to think about being able to offer repeated, large-volume blood-brain barrier-opening treatment — and to do this safely in the setting of delivered therapies like chemotherapy — is a remarkably impressive technological advancement in human health and medicine.”
Unlocking barriers
The blood-brain barrier — a protective layer of interlocking microvascular endothelial cells that line cerebral capillaries — prevents toxins and infectious agents from entering the brain tissue, which could injure the central nervous system.
This historically has posed a challenge of delivering therapies to treat brain tumors.
Glioblastoma is the most common and most aggressive central nervous system tumor.
Most patients undergo surgery, radiotherapy and concomitant temozolomide, followed by an additional six cycles of adjuvant temozolomide.
Prior research suggested less than 20% of temozolomide reaches the brain, according to study background. Patients who receive standard treatment live an average of 14 to 16 months after diagnosis, as residual cancer cells that remain after resection make recurrence inevitable.
“As we increase the safety and extent of tumor removal in neurosurgery, we can improve quality of life and prolong survival, but there is an asymptote to the benefit we can achieve,” Woodworth said. “The problem is, how do we treat the residual brain-invading tumor cells, the component of the tumor that is woven into the fabric of the brain and, in many ways, supported by the functioning neural elements that are key to brain function?
“Improving our understanding of the unique biology of the residual invasive disease and being able to selectively target this component is how we are going to make a dent in glioblastoma,” he added. “For me, focused ultrasound has developed into a tool that can provide access and unlock the barriers to effectively delivering rationally designed therapies and targeting those regions where brain-invading tumor cells have been shielded from therapeutic delivery and effective treatment.”
Focused ultrasound uses sound waves to precisely target and treat tissue deep in the body.
During microbubble-enhanced transcranial focused ultrasound (MB-FUS), small gas-filled bubbles used for ultrasound and echocardiography as a contrast agent are injected into the bloodstream. The bubbles oscillate in the vessels and put pressure on the endothelium, helping to safely and transiently open the blood-brain barrier and allow for delivery of higher concentrations of therapeutic agents to the tumor.
Woodworth and colleagues conducted the multicenter, open-label BT008NA trial at five centers in the U.S. and Canada to evaluate MB-FUS plus standard chemotherapy for patients with newly diagnosed glioblastoma.
Researchers enrolled 34 adults (mean age, 51.5 years; standard deviation, 13; 53% women; 82% white; 100% non-Hispanic) between October 2018 and March 2022.
Median Karnofsky Performance Status score was 90 (range, 70-100). Eighteen patients (53%) had tumors with methylated MGMT promoter status and 29 (85%) had IDH wild-type tumors.
All patients had undergone maximal safe resection and 6 weeks of chemoradiotherapy and were scheduled to begin standard adjuvant temozolomide chemotherapy dosed at 150 mg/m2 on days 1 to 5 of each 28-day cycle.
Researchers delivered MRI-guided MB-FUS treatments — at a frequency of 220 kHz — to tumor-infiltrative regions on any of the first 3 days of each temozolomide cycle for up to six cycles.
Safety and feasibility served as primary outcomes. OS and PFS served as secondary outcomes.
‘Exciting new reality’
Researchers observed blood-brain barrier opening, defined as new contrast enhancement on post-procedure T1-weighted MRI, with all treatments.
Safety analyses showed 176 adverse events; of these, researchers deemed 87 (49%) to be related to MB-FUS (grade 1, n = 40; grade 2, n = 46; grade 3, n = 1).
Two patients died due to adverse events but neither were treatment related. Investigators reported three grade 4 events, all of which were temozolomide-related hematologic abnormalities.
Woodworth and colleagues compared survival outcomes in the intention-to-treat population with those in a control group of 195 patients with glioblastoma who had similar characteristics and received standard temozolomide without focused ultrasound.
Researchers calculated median PFS of 13.5 months (95% CI, 9.9-26.9) in the focused ultrasound cohort and 8.1 months (95% CI, 7.3-9.5) in the control group (P = .02). They calculated median OS of 31.3 months (95% CI, 21.1 to not reached) in the focused ultrasound cohort and 19.3 months (95% CI, 17-22.2) in the control group (P = .0085).
The ability of MB-FUS to increase delivery to temozolomide likely contributed to the efficacy observed. However, neuromodulation and activation of the immune system against the tumor also could play a role, Woodworth said.
“This will need to be a focus in future work,” he said. “We cannot approach this like shooting at a dartboard in the dark. From an efficacy signal perspective, we have to understand how this works.”
The ability to safely open the blood-brain barrier in regions of tumor infiltration creates an opportunity to deliver a variety of therapies, including small-molecule drugs, monoclonal antibodies, antibody-drug conjugates, nanomedicines or even cellular therapies.
“If you can deliver more of the therapy into the brain with this technique, you may not need to dose the patient at such high levels where we otherwise would see toxic effects in the kidneys, the bone marrow or other parts of the body,” Woodworth said. “So we could get increased local delivery but potentially lower systemic side effects.”
Therapies previously considered inappropriate for brain tumor treatment due to low maximum-tolerated doses or their inability to cross the blood-brain barrier could be revisited. Combination strategies — such as pairing immunotherapy with cytotoxic drugs or anti-neuron signaling drugs — also could be explored.
“We can rethink many drugs that have been shelved or not even pushed into clinical trials,” Woodworth said. “That is an exciting new reality.”
‘We have to move forward’
To address FDA concerns about safety, a trial included a subset of patients who consented to have blood drawn prior to and after focused ultrasound to evaluate whether a systemic response to the ultrasound treatment had occurred.
Samples assessed in an unbiased manner at an outside lab showed differences in cell-free DNA that initially appeared “all over the map,” Woodworth said.
In subsequent analyses — after study unblinding of patient outcomes — researchers observed concordance between circulating blood plasma biomarkers — such as DNA fragments — and patient-specific disease courses.
“It was like putting a stencil on top of this random, chaotic design and then seeing a clear image,” Woodworth said. “Remarkably, we saw one pattern in a patient with tumor progression and another pattern in patients with prolonged treatment responses.”
This discovery could enable disease surveillance through ultrasound-enhanced liquid biopsy, allowing for noninvasive assessment of tumor stability and risk for progression or treatment resistance.
“Part of the challenge with glioblastoma is we need to have additional ways to understand if the disease is progressing or responding to therapy,” Woodworth said. “This new approach may allow us to create a monthly adaptive diagnostic and treatment paradigm where the residual invasive disease is targeted for treatment and then the treatment can be evolved month to month based on the continually updated circulating biomarker data. If the MRI and circulating biomarker data suggest the treatment is working, we can keep going, or we can adapt to what we are seeing based on the evolving biomarker pattern.”
Overall, the trial findings demonstrate that the ability to effectively treat malignant brain tumors when they are in a minimal residual disease state could “move the needle” on outcomes for many patients, Woodworth said.
“The current standard treatment has been in place essentially since 2005,” Woodworth said. “Two decades later, a person with a high-grade glioma will have the best possible surgery and then go on to have that protocol. To me, that is not enough. We need to push forward to find ways to do more for our patients, leveraging advanced technologies like image-guided focused ultrasound. This work is a step in that direction.”
For more information:
Graeme F. Woodworth, MD, FAANS, FACS, can be reached at gwoodworth@som.umaryland.edu.
Sources/Disclosures
Source:
Woodworth GF, et al. Lancet Oncol. 2025;doi:10.1016/S1470-2045(25)00492-9.
Disclosures:
NIH and Insightec funded this study. Woodworth reports grants from Focused Ultrasound Foundation, NIH and Maryland Stem Center Research Foundation, as well as clinical trial support from Insightec and the Keep Punching Foundation. Please see the study for all other authors’ relevant financial disclosures.
Ask a clinical question and tap into Healio AI’s knowledge base.
- PubMed, enrolling/recruiting trials, guidelines
- Clinical Guidance, Healio CME, FDA news
- Healio’s exclusive daily news coverage of clinical data
