Ultrasound Technique Delivers Paclitaxel Across Blood-Brain Barrier in Glioblastoma

Glioblastoma brain cancer. Coloured computed tomography (CT) scan of a section through the brain of an 84-year-old female patient with glioblastoma (dark, left). Glioblastoma is the most aggressive form of brain cancer. Treatment involves surgery, after which chemotherapy and radiation therapy are used. However, the cancer usually reoccurs despite treatment and the most common length of survival after diagnosis is 12-15 months. Without treatment, survival is typically 3 months.
An ultrasound technique allows for delivery of albumin-bound paclitaxel across the blood-brain barrier in patients with recurrent glioblastoma, a study suggests.

Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) allows for delivery of albumin-bound paclitaxel across the blood-brain barrier in patients with recurrent glioblastoma, according to research published in The Lancet Oncology

Researchers found that LIPU-MB increased brain parenchymal concentrations of paclitaxel, and the treatment method was considered well tolerated. 

This phase 1 trial (ClinicalTrials.gov Identifier: NCT03744026) included 17 adults with recurrent glioblastoma and a tumor diameter of 70 mm or smaller. The patients’ median age was 57 (range, 52-63) years, and 53% of patients were men. All patients had previously received radiotherapy, and 94% had received temozolomide.

After patients underwent tumor resection, a 9-emitter ultrasound device was implanted into a skull window. The patients then received LIPU-MB with intravenous albumin-bound paclitaxel infusion every 3 weeks for up to 6 cycles. Six dose levels were tested: 40 mg/m², 80 mg/m², 135 mg/m², 175 mg/m², 215 mg/m², and 260 mg/m².

One patient each was treated at the first 5 dose levels, and 12 patients were treated at 260 mg/m2. The median number of chemotherapy cycles per patient was 3. 

A majority of patients (71%) had immediate yet transient grade 1-2 headache. Other grade 1-2 neurological deficits included paresthesia (12%), facial or limb weakness (24%), dysphasia (12%), dysarthria (12%), dysesthesia (18%), and blurred vision (29%). 

“These acute treatment-emergent adverse events were anatomically associated with the brain region being sonicated (eg, sonication of the left temporal LIPU-MB led to transient grade 1 dysphasia),” the researchers noted. 

There was 1 dose-limiting toxicity. It was grade 3 encephalopathy in a patient receiving the 260 mg/m2 dose. Another patient had grade 2 encephalopathy at the 260 mg/m2 dose. In both cases, this toxicity resolved in 1-2 days with supportive care, and both patients were able to continue on treatment with a dose reduction (to 175 mg/m2 and 215 mg/m2, respectively). 

One patient developed grade 2 peripheral neuropathy on the 260 mg/m2 dose, which persisted even after a dose reduction to 215 mg/m2

The most common grade 3-4 treatment-emergent adverse events were neutropenia (47%), leukopenia (29%), and hypertension (29%). There were no treatment-related deaths. 

Pharmacokinetic analyses showed a significant increase in the mean brain parenchymal concentration of albumin-bound paclitaxel from the nonsonicated brain to the sonicated brain (from 0.037 to 0.139 μM; P <.0001). A post hoc analysis suggested restoration of the blood-brain barrier within 1 hour of LIPU-MB. 

At the data cutoff, all patients had experienced disease progression, and 59% of patients had died from disease progression. The median progression-free survival was 2.9 months, and the median overall survival was 11 months.

“Along with several other reports, our findings support the feasibility of LIPU-MB to effectively bypass the blood-brain barrier and treat diseases in the brain, an organ that is beyond the reach of many pharmacological agents,” the researchers concluded. 

They are now testing LIPU-MB for the delivery of albumin-bound paclitaxel and carboplatin in a phase 1/2 trial of patients with glioblastoma (ClinicalTrials.gov Identifier: NCT04528680).

Disclosures: The current study was partly supported by Carthera and Bristol Myers Squibb. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

Sonabend AM, Gould A, Amidei C, et al. Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: A phase 1 trial. Lancet Oncol. Published online May 2023. doi:10.1016/S1470-2045(23)00112-2. 

This article originally appeared on Cancer Therapy Advisor