One-Year Outcome of Multiple Blood-Brain Barrier Disruptions With Temozolomide for the Treatment of Glioblastoma.
Authors: Park SH, Kim MJ, Jung HH, Chang WS, Choi HS, Rachmilevitch I, Zadicario E, Chang JW
<b>Introduction:</b> To overcome the blood-brain barrier (BBB) which interferes with the effect of chemotherapeutic agents, we performed multiple disruptions of BBB (BBBD) with magnetic resonance-guided focused ultrasound on patients with glioblastoma (GBM) during standard adjuvant temozolomide (TMZ) chemotherapy [clinical trial registration no.NCT03712293 (clinicaltrials.gov)]. We report a 1-year follow-up result of BBBD with TMZ for GBM. <b>Methods:</b> From September 2018 to January 2019, six patients were enrolled (four men and two women, median age: 53 years, range: 50-67 years). Of the six patients, five underwent a total of six cycles of BBBD during standard TMZ adjuvant therapy. One patient underwent three cycles of BBBD but continued with TMZ chemotherapy. The 1-year follow-up results of these six patients were reviewed. <b>Results:</b> The mean follow-up duration was 15.17 ± 1.72 months. Two patients showed a recurrence of tumor at 11 and 16 months, respectively. One underwent surgery, and the other patient was restarted with TMZ chemotherapy due to the tumor location with a highly possibility of surgical complications. The survival rate up to 1 year was 100%, and the other four patients are on observation without recurrence. None of the six patients had immediate or delayed BBBD-related complications. <b>Conclusion:</b> Multiple BBBDs can be regarded as a safe procedure without long-term complications, and it seems to have some survival benefits. However, since TMZ partially crosses the BBB, a further extended study with large numbers would be needed to evaluate the benefits of BBBD resulting in an increase of TMZ concentration. This study opened a new therapeutic strategy for GBM by combining BBBD with a larger molecular agent.
Introduction
Purpose
drug delivery with BBB opening
Study Objective
Evaluate 1-year safety and survival outcomes of multiple blood-brain barrier disruptions using MR-guided focused ultrasound combined with temozolomide chemotherapy in patients with glioblastoma
Animal model / Human subject
human
Disease model
glioblastoma
MRI or image guidance method
Yes (MRI + stereotactic)
Targeted brain region(s)
Within 2 Cm Of Tumor Margin (Peritumoral White Matter With High Flair Signal)
Cargo name and characteristics
temozolomide (TMZ, 194 Da, lipophilic, partially crosses BBB)
Route of administration
oral (temozolomide)
Outcomes and Safety
Summary of Outcomes
Six patients with newly diagnosed GBM after gross total resection underwent BBBD during standard 6-cycle adjuvant TMZ. Median follow-up 15.2 months. 1-year survival rate 100%; two patients recurred at 11 and 16 months. No immediate or delayed BBBD-related complications. Four patients remained recurrence-free at last follow-up.
Safety-related matter
No immediate or delayed BBBD-related complications. One patient developed pseudoprogression with mild motor weakness, resolved after steroid therapy; later recurrence. No other adverse events.
Brain Region
Ultrasound Parameters
Ultrasound instrument
ExAblate Neuro Model 4000 Type 2.0 (InSightec), low-frequency MRgFUS system, 220 kHz
FUS Frequency
220kHz
Duration of a single FUS session
210 s per target (approximately 4.4 targets per patient per cycle)
Treatment frequency
multiple sessions (up to 6 cycles, one BBBD per cycle on day 1 or 2 of 28-day TMZ cycle)
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