Novel ultrasound device helps chemotherapy cross blood-brain barrier
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Key takeaways:
- Seventeen patients received albumin-bound paclitaxel infusion every 3 weeks for up to six cycles.
- Ultrasound-based opening the blood-brain barrier resulted in four- to sixfold increases in drug concentrations.
The use of low-intensity pulsed ultrasound with concomitant administration of IV microbubbles can improve the delivery of albumin-bound paclitaxel and carboplatin through the blood-brain barrier, study results showed.
In a first in-human clinical trial, published in The Lancet Oncology, researchers repeatedly permeated large regions of the brain to administer potent forms of chemotherapy using a novel, skull-implantable ultrasound device, researchers wrote.
“This opens a lot of possibilities for treating brain diseases with drugs that are already available,” Adam M. Sonabend, MD, FAANS, associate professor of neurological surgery at Northwestern University Feinberg School of Medicine, told Healio. “These findings have a broad impact, and I hope that this can be leveraged by multiple investigators and physicians exploring novel ways of treating diseases in the brain.”
Background and methodology
Potent chemotherapy agents such as paclitaxel, the standard chemotherapeutic agent for treatment of gliomas, are unable to permeate the blood-brain barrier.
Sonabend and colleagues assessed the safety and pharmacokinetics low-intensity pulsed ultrasound with concomitant administration of IV microbubbles (LIPU-MB) to improve the delivery of albumin-bound paclitaxel to the peritumoral brain in patients with recurrent glioblastoma.
The phase 1 dose-escalation trial included adults with recurrent glioblastoma, a tumor diameter of 70 mm or smaller and a Karnofsky performance status of at least 70.
Following tumor resection, researchers implanted a nine-emitter ultrasound device into the skulls of 17 patients (nine men, eight women) to perform LIPU-MB with IV albumin-bound paclitaxel every 3 weeks for up to six cycles.
Researchers evaluated six dose levels: 40 mg/m², 80 mg/m², 135 mg/m², 175 mg/m², 215 mg/m² and 260 mg/m². Twelve patients received the 260 mg/m² dose level and one patient each received the other dose levels.
Dose-limiting toxicity during the first cycle of sonication and albumin-bound paclitaxel chemotherapy served as the primary endpoint.
Median follow-up was 11.89 months.
Results
Researchers administered a total of 68 LIPU-MB-based cycles through the blood-brain barrier (median cycles per patient, 3; range, 2-6).
At the 260 mg/m² dose, one patient experienced grade 3 encephalopathy during the first cycle and one patient had grade 2 encephalopathy during the second cycle. The toxicity resolved and both patients continued treatment at a lower dose: 175 mg/m² for the patient who experienced grade 3 encephalopathy and 215 mg/m² for the patient who experienced grade 2 encephalopathy.
A single patient experienced grade 2 peripheral neuropathy during the third cycle of 260 mg/m² albumin-bound paclitaxel. Researchers reported no progressive neurologic deficits attributed to LIPU-MB.
Immediate yet transient grade 1 to grade 2 headache (71% of patients) occurred most commonly with LIPU-MB-based blood-brain barrier opening, with the most common grade 3 to grade 4 treatment-emergent adverse events being neutropenia (47%), leukopenia (29%) and hypertension (29%). No treatment-related deaths occurred.
Imaging analysis showed brain-blood barrier opening in parts of the brain targeted by LIPU-MB that attenuated over the first hour after sonication.
Pharmacokinetic analyses among a subgroup of patients in the current study and a subgroup who received carboplatin in a similar study showed LIPU-MB resulted in an increase in the mean brain parenchymal concentrations of albumin-bound paclitaxel, from 0.037 M (95% CI, 0.022-0.063) in the nonsonicated brain to 0.139 M (95% CI, 0.083-0.232) in the sonicated brain, and an increase in mean brain parenchymal concentrations of carboplatin from 0.991 M (95% CI, 0.562-1.747) in the nonsonicated brain to 5.878 M (95% CI, 3.462-9.98) in the sonicated brain.
Next steps
Researchers have already begun work in a phase 2 trial to further investigate the effectiveness of drugs delivered through this method.
“The most immediate impact of these findings is that these led to us an ongoing phase 2 clinical trial, where we are now combining two drugs, carboplatin and paclitaxel, and investigating whether these prolong the life of patients with recurrent glioblastoma,” Sonabend told Healio. “Another important implication of our study is that its findings help refine the design of other clinical trials evaluating this approach to deliver drugs to the brain. Scientists should now be aware that timing of drug infusion relative to brain sonication is key to maximize the penetration of drugs into the brain with this approach.”
For more information:
Adam M. Sonabend, MD, FAANS, can be reached at Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611; email: adam.sonabend@northwestern.edu.
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