One-Year Outcome of Multiple Blood-Brain Barrier Disruptions With Temozolomide for the Treatment of Glioblastoma

Abstract

Introduction: 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. Methods: 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. Results: 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. Conclusion: 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.

Keywords: blood–brain barrier; focused ultrasound; glioblastoma multiforme; magnetic resonance images; progression-free survival.

Figure 1

Overview of the study. CCRT, concurrent chemoradiation therapy; BBBD, blood–brain barrier disruption; TMZ, temozolomide; MRI, magnetic resonance imaging.

Figure 2

Axial MRI images at pretreatment and at 1 year after the chemotherapy of patients 2, 3, 4, and 5. (A,B) Pre- and post-treatment MRI of patient 2, respectively. (C,D) Pre- and post-treatment MRI of patient 3, respectively. (E,F) Pre- and post-treatment MRI of patient 4, respectively. (G,H) Pre- and post-treatment MRI of patient 5, respectively.

Figure 3

Pseudoprogression and recurrence of glioblastoma (GBM) in patient 1 after six cycles of adjuvant temozolomide (TMZ) chemotherapy and blood–brain barrier disruption. After the six cycles of adjuvant TMZ chemotherapy, a newly developed enhanced lesion at the left cingulate gyrus was observed on contrast-enhanced T1-weighted MRI (A). However, relative cerebral blood volume (B) and volume transfer coefficient (Ktrans) (C) maps showed no increase of metrics, suggesting pseudoprogression. At 4 months later, MRI was performed due to the reappearance of symptoms. On contrast-enhanced T1-weighted MRI (D), a larger enhanced mass with elevated Ktrans (E) and increased cerebral blood volume (F) are shown.

Figure 4

Axial MRI images of patient 6 at 3 months (before chemotherapy), 9 months (after the completion of chemotherapy), and 11 months after the initial diagnosis of glioblastoma, respectively.