This new technology provides the first evidence of a chemotherapy drug reaching a glioblastoma.
An ultrasound device implanted in the skull and intravenous microbubbles enable researchers to open the blood-brain barrier and target glioblastoma with chemotherapy for the first time.
Treatment of aggressive malignant gliomas has long been hindered by the inability of most strong chemotherapy drugs to cross the blood-brain barrier.
Now researchers have been able to use low-intensity pulsations of ultrasound to open the blood-brain barrier and deliver albumin-bound paclitaxel into the brains of patients with recurrent glioblastoma.
“Large size drugs that previously were not used for gliomas could now be considered for the treatment of diseases in the brain, including glioblastoma,” the researchers wrote in The Lancet Oncology this month.
The researchers said they demonstrated drug penetration to a brain area nine times larger than in previous studies, which is more closely reflective of the treatment area for post-surgical chemotherapy. The chemotherapy was able to reach deep, critical brain areas including the thalamus and basal ganglia.
In the dose-escalation phase I clinical trial, 17 adults with recurrent glioblastoma with a diameter of 70mm or smaller were implanted with ultrasound devices in their skulls after tumour resection.
The researchers monitored blood-brain barrier opening, safety and pharmacokinetics during the sonication-coupled chemotherapy with either albumin-bound paclitaxel or carboplatin. These cytotoxic agents have previously been associated with neurotoxicity when administered to the brain via injection.
Participants had an average of three treatment cycles.
Brain concentrations of the drugs increased between three and six times after when administered with sonication, depending on the molecular weight of the drug, they said.
“We report that large-volume blood–brain barrier opening is safe, reproducible, and can be repeated over multiple cycles of chemotherapy,” the researchers said.
The most common side-effect was transient headache which 71% of patients experienced, and the most common adverse events were neutropenia (47% of patients), leukopenia (29%) and hypertension (29%).
There were no treatment-related deaths during the 12-month follow-up period and no progressive neurological deficits associated with the technique, the authors said.
The researchers said the blood-brain barrier was restored within 30 to 60 minutes after they stopped sonication, which showed there was a critical time window in which to administer drugs.
They also noted that the method may fall short in the case of larger tumours due to the limited scale for the device, despite being larger than previous devices, and the dynamics of the drugs following low-intensity pulsed ultrasound remain poorly characterised, they said.
A follow-up phase 2 study investigating treatment with a combination of paclitaxel and carboplatin is currently underway.