麻豆传媒

Use of a novel skull-implantable ultrasound device was able to open the blood-brain barrier, which allowed for penetration of albumin-bound paclitaxel into critical regions of the brain in patients with glioblastoma, a dose-escalation phase I trial showed.

Looking at low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) with six dose levels of intravenous albumin-bound paclitaxel ranging from 40 to 260 mg/m², no dose-limiting toxicities were observed for escalating dose levels up to 215 mg/m², reported Adam M. Sonabend, MD, of the Feinberg School of Medicine at Northwestern University in Chicago, and colleagues.

At a dose of 260 mg/m², grade 3 encephalopathy occurred in one of 12 patients during the first cycle, which was considered a dose-limiting toxicity, and grade 2 encephalopathy occurred in one patient during the second cycle. In both cases, the toxicity resolved and treatment continued at a lower dose (175 mg/m² in the case of grade 3 encephalopathy and 215 mg/m² in the case of grade 2 encephalopathy), they noted in .

Grade 2 peripheral neuropathy was also observed in one patient during the third cycle with a 260 mg/m² dose.

There were no surgical complications or infections related to implanting the device. Sonabend and team reported that 68 cycles of LIPU-MB-based blood-brain barrier opening were performed across all patients, with a median of 3 cycles per patient.

According to Sonabend and colleagues, the inability of most drugs to cross the blood-brain barrier limits treatment options for brain diseases. They pointed out that while paclitaxel is approximately 1,400 times more potent than temozolomide -- the standard chemotherapeutic agent for gliomas -- it does not cross the blood-brain barrier, unlike temozolomide.

With the use of LIPU-MB, intravenously administered microbubbles oscillate in brain capillaries upon stimulation by ultrasound, generating mechanical stress on the endothelial wall that opens the blood-brain barrier. It has been shown to work in animal models and early clinical trials.

"Results from this phase I clinical trial suggest that ultrasound treatments can enhance chemotherapeutic delivery of different agents by up to six times in patients with brain tumors," wrote Antonios N. Pouliopoulos, MSc, PhD, of King's College London, in a . "This outcome further emphasizes the potential for therapeutic ultrasound to enhance the treatment effect of new and existing drugs."

"Agents deemed to have inadequate efficacy in clinical trials because of their inability to cross the blood-brain barrier, including antibodies and liposomes, could be reused in conjunction with ultrasound treatments," he added.

No progressive neurological deficits attributed to LIPU-MB were observed in the study. LIPU-MB-based blood-brain barrier opening was most commonly associated with immediate, yet transient, grade 1-2 headache (12 of 17 patients), and other grade 1-2 neurological deficits, such as paresthesia (12%), facial or limb weakness (24%), dysphasia (12%), dysarthria (12%), dysesthesia (18%), and blurred vision (29%).

The most common grade 3-4 treatment-emergent adverse events were neutropenia (47%), leukopenia (29%), and hypertension (29%).

Additionally, pharmacokinetic analyses of seven patients who received paclitaxel, and three patients who received carboplatin in a , showed that use of LIPU-MB led to substantial increases in the chemotherapy concentration in the brain parenchyma.

Specifically, serial biopsy samples in peritumoral areas treated with ultrasound showed that the mean brain tissue concentration of paclitaxel was 3.7 times higher than in non-sonicated brain tissue (0.139 μM vs 0.037 μM, P<0.0001), while the mean absolute brain carboplatin concentration was 5.9 times higher (5.878 μM vs 0.991 μM, P=0.0001).

The investigators' analyses also showed that blood-brain barrier integrity is mostly restored within an hour after LIPU-MB.

"Our trial results have led us to investigate LIPU-MB for the delivery of albumin-bound paclitaxel plus carboplatin for glioblastoma in an ongoing ," Sonabend and colleagues wrote. "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."

While the study suggests ultrasound treatments can enhance chemotherapeutic delivery of different agents, Pouliopoulos noted in his commentary that "evidence of increased drug concentration following ultrasound treatment is not sufficient for clinical adoption."

"Future phase II and III randomized clinical trials are needed to establish whether ultrasound-mediated drug delivery increases progression-free and overall survival," he wrote. "However, designing such trials is challenging, given the ethical barriers of active control trials that include groups of patients not treated with state-of-the-art regimens."

For this study, 17 adult patients with recurrent glioblastoma, a tumor diameter of ≤70 mm, and a Karnofsky performance status of at least 70 were enrolled from October 2020 to February 2022. Median age was 57, 53% were men, and 94% were white. They underwent resection of their tumors and implantation of the ultrasound device, and then started treatment within 3 weeks of implantation.

LIPU-MB with intravenous albumin-bound paclitaxel infusion was done every 3 weeks for up to six cycles. Dose levels of 40 mg/m², 80 mg/m², 135 mg/m², 175 mg/m², 215 mg/m², and 260 mg/m² were evaluated.

Median follow-up was 11.89 months. One patient was treated per dose level of albumin-bound paclitaxel for levels 1 to 5 (40-215 mg/m²), and 12 patients were treated at dose level 6 (260 mg/m²).

The primary endpoint was dose-limiting toxicity occurring during the first cycle of sonication and albumin-bound paclitaxel chemotherapy.

At data cutoff, all patients experienced disease progression, and 10 of 17 patients died due to disease progression. In a post-hoc descriptive analysis, median progression-free survival was 2.9 months, and median overall survival was 11 months.

Upon progression, three patients did not receive additional treatment due to poor clinical condition, seven underwent additional tumor resection, 10 received immunotherapy, five received chemotherapy, and 12 received bevacizumab (Avastin).

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