Levetiracetam as a sensitizer of concurrent chemoradiotherapy in newly diagnosed glioblastoma: An open‐label phase 2 study

Hwang, Kihwan; Kim, Junhyung; Kang, Seok‐Gu; Jung, Tae‐Young; Kim, Jeong Hoon; Kim, Se-Hyuk; Kang, Shin‐Hyuk; Hong, Young Sun; Kim, Tae Min; Kim, Yu Jung; Choi, Byung Se; Chang, Jong Hee; Kim, Chae-Yong

doi:10.1002/cam4.4454

Cited by 12 publications

(8 citation statements)

References 36 publications

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“…Despite advances in chemotherapy therapy, patients with GBM who have undergone surgery are confronted by drug resistance and tumor recurrence; these factors can lead to immense physical and financial stress. Hwang et al reported the negative results for patients with GBM in their clinical trial for LEV on the survival benefits of patients with GBM in 2022 [ 19 ], which is opposite to their observational study [ 30 ]. However, this study was limited by its single-arm design.…”

Section: Discussionmentioning

confidence: 99%

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The efficacy of temozolomide combined with levetiracetam for glioblastoma (GBM) after surgery: a study protocol for a double-blinded and randomized controlled trial

Sun

Huang

Tao

et al. 2022

Trials

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Background Temozolomide is applied as the standard chemotherapy agent in patients with glioblastoma (GBM) after surgery. However, the benefit of this treatment for patients is limited by the invasive growth of gliomas and drug resistance. There are indications from fundamental experimental and retrospective studies that levetiracetam has the potential to improve the survival rate of patients with GBM. However, it has yet to be determined whether the combination of temozolomide and levetiracetam is more effective than standard temozolomide chemotherapy. Therefore, we designed a randomized clinical trial to investigate the therapeutic effect of the new combined regime for treating GBM. Methods/design This is a double-blind and randomized clinical trial conducted in a single center. One hundred forty-two patients will be recruited and screened for the inclusion and exclusion criteria. Then, eligible participants will be randomly assigned to an experimental group or a control group in a 1:1 ratio. Based on the administration of radiation therapy (RT), participants in the experimental group will be prescribed levetiracetam plus temozolomide chemotherapy for 34 weeks while participants in the control group will receive placebo tablets plus temozolomide for the same duration. A 3-year follow-up will be conducted on all patients after intervention. Accordingly, the primary outcome will be progression-free survival (PFS). The secondary endpoints include overall survival (OS), the Karnofsky Performance Status (KPS), the objective response rate (ORR), and adverse event incidence. Discussion It is expected that the results of this trial will provide high-level evidence regarding the clinical benefits of levetiracetam and temozolomide combined in the treatment of GBM. Trial registration Chinese Clinical Trial Registry, ChiCTR2100049941. Registered on 14 August 2021

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Section: Discussionmentioning

confidence: 99%

“…No differences were found in survival as a result of LEV. LEV had no significant side effects or overdose symptoms in the study, even when patients received an increased dose of up to 2000 mg/day and other AEDs as well [ 19 ]. However, the study was limited by a single-arm study design with external and historical control.…”

Section: Introductionmentioning

confidence: 99%

The efficacy of temozolomide combined with levetiracetam for glioblastoma (GBM) after surgery: a study protocol for a double-blinded and randomized controlled trial

Sun

Huang

Tao

et al. 2022

Trials

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“…The presence of glioma-neuron interactions has now been established, however there are likely multiple mechanisms driving synaptogenesis and non-synaptic peritumoral hyperexcitability. 39–41 Whether treatment aimed at reducing neuronal firing impacts the clinical course of disease, as suggested in animal models and some small retrospective cohorts, 5,12–15,17 remains uncertain. For example, early glioma-related hyperexcitability in clinical EEG recordings has been associated with decreased overall survival despite treatment with ASMs, 42 while meta-analysis and a large pooled study of contemporary clinical trials for glioblastoma found no associations between the use of valproic acid or levetiracetam and survival outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…However, post hoc analyses in neuro-oncology cohorts evaluating tumor outcomes associated with ASM exposure have provided conflicting results and have been inherently limited by indication bias. [8][9][10][11][12][13][14][15][16][17][18][19] The selective post-synaptic AMPA-R antagonists, talampanal and perampanel, have demonstrated promising anti-seizure effects, [20][21][22][23][24] although their impact on clinical tumor outcomes remains uncertain. [17][18][19] Furthermore, it is unclear whether targeting glutamatergic signaling provides an advantage over targeting other mechanisms of excessive synaptic activity with first-line broad-spectrum ASMs such as levetiracetam.…”

Section: Introductionmentioning

confidence: 99%

Pilot trial of perampanel on peritumoral hyperexcitability and clinical outcomes in newly diagnosed high-grade glioma

Tobochnik,

Regan,

Dorotan

et al. 2024

Preprint

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Background Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the AMPA-R antagonist, perampanel, on intraoperative electrophysiologic hyperexcitability and clinical outcomes. Methods An open-label trial was performed comparing perampanel to standard of care (SOC) in patients undergoing resection of newly-diagnosed radiologic high-grade glioma. Perampanel was administered as a pre-operative loading dose followed by maintenance therapy until progressive disease or up to 12-months. SOC treatment involved levetiracetam for 7-days or as clinically indicated. The primary outcome of hyperexcitability was defined by intra-operative electrocorticography high frequency oscillation (HFO) rates. Seizure-freedom and overall survival (OS) were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and metabolites were measured by mass spectrometry. Results HFO rates were similar between perampanel-treated and SOC cohorts. The trial was terminated early after interim analysis for futility, and outcomes assessed in 11 patients (7 perampanel-treated, 4 SOC). Over a median 281 days of post-enrollment follow-up, 27% of patients had seizures, including 14% treated with perampanel and 50% treated with SOC. OS in perampanel-treated patients was similar to a glioblastoma reference cohort (p=0.81). Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations. Conclusions A peri-operative loading regimen of perampanel was safe and well-tolerated, with similar peritumoral hyperexcitability as in levetiracetam-treated patients. Maintenance anti-glutamatergic therapy was not observed to impact survival outcomes.

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“…Levetiracetam (LEV), a relatively new antiepileptic drug, modulates HDAC levels ultimately silencing MGMT, thus increasing TMZ effectiveness in GCSs [ 224 ]. Retrospective analyses and an open-label phase II study (NCT02815410) seem to evidence that LEV improves GB patients’ PFS and OS [ 225 , 226 ]. So, it is perhaps time to reconsider the results performed in 2016, where a pooled analysis of a large series of cases treated with valproic acid or levetiracetam failed to find an association with patients’ survival [ 227 ].…”

Section: Lessons Learned In the Pathophysiology Of Glioblastomamentioning

confidence: 99%

Glioblastoma Therapy: Past, Present and Future

Obrador,

Moreno-Murciano,

Oriol-Caballo

et al. 2024

IJMS

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Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms involved in GB growth, aggressiveness and recurrence. The discussion on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different signaling pathways (pRB/CDK4/RB1/P16ink4, TP53/MDM2/P14arf, PI3k/Akt-PTEN, RAS/RAF/MEK, PARP) involved in GB tumorigenesis, pathophysiology, and treatment resistance acquisition. Below, we analyze several immunotherapeutic approaches (i.e., checkpoint inhibitors, vaccines, CAR-modified NK or T cells, oncolytic virotherapy) that have been used in an attempt to enhance the immune response against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, we present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or sensitizers, radionuclides, and molecules that target GB cellular receptors or open the blood–brain barrier) and non-ionizing energies (laser interstitial thermal therapy, high/low intensity focused ultrasounds, photodynamic/sonodynamic therapies and electroporation). The aim of this review is to discuss the advances and limitations of the current therapies and to present novel approaches that are under development or following clinical trials.

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Levetiracetam as a sensitizer of concurrent chemoradiotherapy in newly diagnosed glioblastoma: An open‐label phase 2 study

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 12 publications

References 36 publications

The efficacy of temozolomide combined with levetiracetam for glioblastoma (GBM) after surgery: a study protocol for a double-blinded and randomized controlled trial

The efficacy of temozolomide combined with levetiracetam for glioblastoma (GBM) after surgery: a study protocol for a double-blinded and randomized controlled trial

Pilot trial of perampanel on peritumoral hyperexcitability and clinical outcomes in newly diagnosed high-grade glioma

Glioblastoma Therapy: Past, Present and Future

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