scholarly journals RADT-46. SYSTEMATIC REVIEW OF RADIOSENSITIZERS FOR MALIGNANT BRAIN TUMORS: POTENTIAL FOR LEARNING FROM PAST FAILURES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii191-ii191
Author(s):  
Usman Beg ◽  
Brianna Snyder ◽  
Sarosh Madhani ◽  
Nima Hamidi ◽  
Alireza Mansouri
Keyword(s):  
Systematic Review ◽  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Mechanism Of Action ◽  
Progression Free Survival ◽  
Tumor Oxygenation ◽  
Cns Tumors ◽  
Brain Barrier ◽  
Research Progress ◽  
Blood Brain

Abstract INTRODUCTION Radiation therapy (RT) is the cornerstone of management of malignant CNS tumors but its efficacy is limited in hypoxic tumors. Although numerous radiosensitizer compounds have been developed to enhance the effect of RT, progress has been stagnant. Through this systematic review of the literature on radiosensitizers for malignant CNS tumors, we have sought to provide an overview of radiosensitizers developed to date, summarize their safety and efficacy, and evaluate areas for possible improvement. METHODS PUBMED, EMBASE, Cochrane, and Web of Science were searched using terminology pertaining to radiosensitizers for brain tumor RT according to PRISMA guidelines. Publications reporting clinical evidence of non-antineoplastic radiosensitizers with RT for malignant CNS tumors were included. Pre-specified variables were extracted. Outcomes of interest were overall survival, progression-free survival, adverse events, and quality-of-life outcomes. RESULTS Forty-eight publications were identified which included 20 unique non-antineoplastic radiosensitizing agents. Only 2/20 agents, fluosol with oxygen, and efaproxiral, showed improvement in outcomes in patients with glioblastoma and brain metastasis, respectively. A larger study was not able to confirm the latter. While molecular similarities between these two agents were not identifiable, the effective mechanism of action allowed them to modulate hypoxia from within blood vessels, without crossing blood-brain barrier. Nine agents required dose modification, change of schedule, or complete discontinuation due to toxicities. CONCLUSION Despite decades of research, progress in the field of radiosensitizers for malignant CNS tumors has been limited. Available data demonstrates the lack of progress in identifying effective radiosensitizers for brain tumors. Of the many non-antineoplastic radiosensitizers that have been tested, only two have showed (limited) efficacy by targeting tumor oxygenation. Alternative strategies such as synthetic drug design, based on a mechanism of action that is independent of crossing the blood-brain barrier, may be necessary. Such studies are currently underway.

Hyperosmolar blood-brain barrier disruption in baboons: an in vivo study using positron emission tomography and rubidium-82

1996 ◽  
Vol 84 (3) ◽  
pp. 494-502 ◽  
Author(s):  
Bernhard Zünkeler ◽  
Richard E. Carson ◽  
Jeffrey Olson ◽  
Ronald G. Blasberg ◽  
Mary Girton ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Emission Tomography ◽  
Brain Barrier ◽  
Blood Brain ◽  
Positron Emission ◽  
The Mean ◽  
Rubidium 82

✓ Hyperosmolar blood-brain barrier (BBB) disruption remains controversial as an adjuvant therapy to increase delivery of water-soluble compounds to extracellular space in the brain in patients with malignant brain tumors. To understand the physiological effects of BBB disruption more clearly, the authors used positron emission tomography (PET) to study the time course of BBB permeability in response to the potassium analog rubidium-82 (82Rb, halflife 75 seconds) following BBB disruption in anesthetized adult baboons. Mannitol (25%) was injected into the carotid artery and PET scans were performed before and serially at 8- to 15-minute intervals after BBB disruption. The mean influx constant (K1), a measure of permeability-surface area product, in ipsilateral, mannitol-perfused mixed gray- and white-matter brain regions was 4.9 ± 2.4 µl/min/ml (± standard deviation) at baseline and increased more than 100% (ΔK1 = 9.4 ± 5.1 µl/min/ml, 18 baboons) in brain perfused by mannitol. The effect of BBB disruption on K1 correlated directly with the total amount of mannitol administered (p < 0.005). Vascular permeability returned to baseline with a halftime of 24.0 ± 14.3 minutes. The mean brain plasma volume rose by 0.57 ± 0.34 ml/100 ml in ipsilateral perfused brain following BBB disruption. This work provides a basis for the in vivo study of permeability changes induced by BBB disruption in human brain and brain tumors.

scholarly journals Marizomib alone or in combination with bevacizumab in patients with recurrent glioblastoma: phase I/II clinical trial data

2021 ◽  
Author(s):  
Daniela A Bota ◽  
Warren Mason ◽  
Santosh Kesari ◽  
Rajiv Magge ◽  
Benjamin Winograd ◽  
...  
Keyword(s):  
Phase I ◽  
Blood Brain Barrier ◽  
Dose Escalation ◽  
Safety Profile ◽  
Clinical Trial Data ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Brain Barrier ◽  
Part C ◽  
Blood Brain

Abstract Background This phase I/II trial in patients with recurrent glioblastoma (GBM) evaluates the safety and preliminary efficacy of marizomib, an irreversible pan-proteasome inhibitor that crosses the blood–brain barrier. Patients and Methods Part A assessed the safety and efficacy of marizomib monotherapy. In Part B, escalating doses of marizomib (0.5–0.8 mg/m2) in combination with bevacizumab were evaluated. Part C explored intra-patient dose escalation of marizomib (0.8–1.0 mg/m2) for the combination. Results In Part A, 30 patients received marizomib monotherapy. The most common AEs were fatigue (66.7%), headache (46.7%), hallucination (43.3%), and insomnia (43.3%). One patient (3.3%) achieved a partial response. In Part B, the recommended phase II dose of marizomib was 0.8 mg/m2 when combined with bevacizumab 10 mg/kg. In Part C, dose escalation to 1.0 mg/m2 was not tolerated. Pooled analysis of 67 patients treated with marizomib ≤0.8 mg/m2 and bevacizumab showed a non-overlapping safety profile consistent with the known safety profile of each agent: the most common grade ≥3 AEs were hypertension (16.4%), confusion (13.4%), headache (10.4%), and fatigue (10.4%). The overall response rate was 34.3%, including 2 patients with complete response. Six-month progression-free survival was 29.8%; median overall survival was 9.1 months. Conclusions The safety profile of marizomib as monotherapy and in combination with bevacizumab was consistent with previous observations that marizomib crosses the blood–brain barrier. Preliminary efficacy did not demonstrate a meaningful benefit of the addition of marizomib to bevacizumab for the treatment of recurrent GBM.

Quantification and pharmacokinetics of blood-brain barrier disruption in humans

1996 ◽  
Vol 85 (6) ◽  
pp. 1056-1065 ◽  
Author(s):  
Bernhard Zünkeler ◽  
Richard E. Carson ◽  
Jeff Olson ◽  
Ronald G. Blasberg ◽  
Hetty Devroom ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Normal Brain ◽  
Content Type ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption ◽  
Fine Print

✓ Hyperosmolar blood-brain barrier disruption (HBBBD), produced by infusion of mannitol into the cerebral arteries, has been used in the treatment of brain tumors to increase drug delivery to tumor and adjacent brain. However, the efficacy of HBBBD in brain tumor therapy has been controversial. The goal of this study was to measure changes in vascular permeability after HBBBD in patients with malignant brain tumors. The permeability (K1) of tumor and normal brain blood vessels was measured using rubidium-82 and positron emission tomography before and repeatedly at 8- to 15-minute intervals after HBBBD. Eighteen studies were performed in 13 patients, eight with glioblastoma multiforme and five with anaplastic astrocytoma. The HBBBD increased K1 in all patients. Baseline K1 values were 2.1 ± 1.4 and 34.1 ± 22.1 µl/minute/ml (± standard deviation) for brain and tumor, respectively. The peak absolute increases in K1 following HBBBD were 20.8 ± 11.7 and 19.7 ± 10.7 µl/minute/ml for brain and tumor, corresponding to percentage increases of approximately 1000% in brain and approximately 60% in tumor. The halftimes for return of K1 to near baseline for brain and tumor were 8.1 ± 3.8 and 4.2 ± 1.2 minutes, respectively. Simulations of the effects of HBBBD made using a very simple model with intraarterial methotrexate, which is exemplary of drugs with low permeability, indicate that 1) total exposure of the brain and tumor to methotrexate, as measured by the methotrexate concentration-time integral (or area under the curve), would increase with decreasing infusion duration and would be enhanced by 130% to 200% and by 7% to 16%, respectively, compared to intraarterial infusion of methotrexate alone; and 2) exposure time at concentrations above 1 µM, the minimal concentration required for the effects of methotrexate, would not be enhanced in tumor and would be enhanced by only 10% in brain. Hyperosmolar blood-brain barrier disruption transiently increases delivery of water-soluble compounds to normal brain and brain tumors. Most of the enhancement of exposure results from trapping the drug within the blood-brain barrier, an effect of the very transient alteration of the blood-brain barrier by HBBBD. Delivery is most effective when a drug is administered within 5 to 10 minutes after disruption. However, the increased exposure and exposure time that occur with methotrexate, the permeability of which is among the lowest of the agents currently used clinically, are limited and the disproportionate increase in brain exposure, compared to tumor exposure, may alter the therapeutic index of many drugs.

Blood–Brain Barrier and Edema in Brain Tumors

Brain Edema ◽  
2017 ◽  
pp. 293-313 ◽  
Author(s):  
Andreas F. Mack ◽  
Hartwig Wolburg ◽  
Petra Fallier-Becker
Keyword(s):  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain
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