In a small single-institution phase I trial reported in The Lancet Oncology, Sonabend et al found that an implantable device for low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) may be safely used to open the blood-brain barrier to permit increased peritumoral delivery of chemotherapy in patients with recurrent glioblastoma.
Study Details
Seventeen patients were enrolled into the study at Northwestern University Feinberg School of Medicine between October 2020 and February 2022. Patients had the ultrasound device implanted into a skull window after tumor resection. LIPU-MB with albumin-bound paclitaxel infusion was performed every 3 weeks at six dose levels for up to six cycles; 1 patient each received 40, 80, 135, 175, and 215 mg/m², and 12 received 260 mg/m². The primary endpoint was dose-limiting toxicity in the first cycle of sonication and albumin-bound paclitaxel chemotherapy. Blood-brain barrier opening was investigated by magnetic resonance imaging before and after sonication. Pharmacokinetic analyses of LIPU-MB were performed in a subgroup of study patents and in a subgroup of patients who received carboplatin via this method in a similar trial.
Key Findings
Median follow-up was 11.89 months (interquartile range = 11.12–12.78 months).
A total of 68 cycles of LIPU-MB–based blood-brain barrier opening were performed (median = 3 cycles per patient; range = 2–6). No complications or infections attributed to the implanted device were observed.
At a dose of 260 mg/m², grade 3 encephalopathy occurred in 1 (8%) of 12 patients during the first cycle and constituted a dose-limiting toxicity. Grade 2 encephalopathy occurred in 1 patient during the second cycle. In both cases, toxicity resolved and treatment continued at a lower dose of albumin-bound paclitaxel (175 mg/m² in the patient with grade 3 encephalopathy and 215 mg/m² in the patients with grade 2 encephalopathy.
Grade 2 peripheral neuropathy was observed in one patient during the third cycle of 260 mg/m² albumin-bound paclitaxel. No progressive neurological deficits attributed to LIPU-MB were observed. LIPU-MB–based blood-brain barrier opening was most commonly associated with immediate—yet transient—grade 1 or 2 headache, observed in 12 (71%) of 17 patients. The most common grade 3 or 4 adverse events were neutropenia (47%), leukopenia (29%), and hypertension (29%). No treatment-related deaths occurred.
Blood-brain barrier openings in the regions targeted by LIPU-MB diminished over the first hour after sonication. Pharmacokinetic analyses showed that LIPU-MB led to a 3.7 times increase in the mean brain parenchymal concentrations of albumin-bound paclitaxel, from 0.037 μM (95% confidence interval [CI] = 0.022–0.063 µM) in nonsonicated brain to 0.139 μM (95% CI = 0.083–0.232 µM) in sonicated brain (P < .0001) and a 5.9 times increase in carboplatin concentration, from 0.991 μM (95% CI = 0.562–1.747 µM) in nonsonicated brain to 5.878 μM (95% CI = 3.462–9.980 μM) in sonicated brain (P = .0001).
The investigators concluded, “LIPU-MB using a skull-implantable ultrasound device transiently opens the blood-brain barrier allowing for safe, repeated penetration of cytotoxic drugs into the brain. This study has prompted a subsequent phase II study combining LIPU-MB with albumin-bound paclitaxel plus carboplatin (NCT04528680), which is ongoing.”
Adam M. Sonabend, MD, of the Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the National Institutes of Health and National Cancer Institute, the Moceri Family Foundation, and the Panattoni family. For full disclosure of the study authors, visit thelancet.com.
