Temozolomide and seizure outcomes in a randomized clinical trial of elderly glioblastoma patients

Climans, Seth A; Brandes, Alba Ariela; Cairncross, J. Gregory; Ding, Keyue; Fay, Michael; Laperrière, Normand; Menten, Johan; Nishikawa, Ryo; O’Callaghan, Christopher J.; Perry, James; Phillips, Claire; Roa, Wilson; Wick, Wolfgang; Winch, Chad; Mason, Warren P.

doi:10.1007/s11060-020-03573-x

Cited by 16 publications

(18 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These pathways are known to encourage tumor growth, and so their interruption would restrict the ability of enduring tumor cells to progress into fully-fledged recurrent GBMs. However, other recent evidence suggests that the addition of TMZ to RT has a minimal effect on seizure presence in elderly GBM patients vs. RT alone (Climans et al, 2020 ). Climans et al ( 2020 ) also demonstrated that decreased overall survival was significantly associated with seizures.…”

Section: From Laboratory To Clinical Translationmentioning

confidence: 99%

“…However, other recent evidence suggests that the addition of TMZ to RT has a minimal effect on seizure presence in elderly GBM patients vs. RT alone (Climans et al, 2020 ). Climans et al ( 2020 ) also demonstrated that decreased overall survival was significantly associated with seizures. This paradoxically supports the hypothesis that continuous seizure presence and associated excitotoxicity may increase the likelihood of tumor recurrence, and subsequently decrease the overall survival of epileptogenic GBM patients relative to patients without seizures.…”

Section: From Laboratory To Clinical Translationmentioning

confidence: 99%

“…This former connection is primarily based on the hypothesis that seizures provoke earlier tumor discovery and initiation of anti-tumorigenic treatment, translating to increased survival. Yet, recent clinical evidence has indicated a significant association between new-onset seizures post-GBM diagnosis and mortality in IDH-wildtype GBM patients (Climans et al, 2020 ; Wasade et al, 2020 ; Mastall et al, 2021 ). This disparity suggests that the mechanisms underlying seizure occurrence at these respective time points may slightly differ in their progression.…”

Section: The Importance Of Timingmentioning

confidence: 99%

“…Testing novel treatments in a model of GBM that does not account for seizure presence may confound results by omitting to include a potentially important influencer of therapeutic efficacy that affects a substantial portion of the patient population. Examples of how clinically-used anti-tumor treatments affect seizures in GBM have been examined in clinical trials (Chalifoux and Elisevich, 1997 ; Climans et al, 2020 ), but the literature primarily focuses on low-grade gliomas.…”

Section: From Laboratory To Clinical Translationmentioning

confidence: 99%

See 3 more Smart Citations

Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

Hills

Kostarelos

Wykes

2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Glioblastoma (GBM) is the most common and advanced form of primary malignant tumor occurring in the adult central nervous system, and it is frequently associated with epilepsy, a debilitating comorbidity. Seizures are observed both pre- and post-surgical resection, indicating that several pathophysiological mechanisms are shared but also prompting questions about how the process of epileptogenesis evolves throughout GBM progression. Molecular mutations commonly seen in primary GBM, i.e., in PTEN and p53, and their associated downstream effects are known to influence seizure likelihood. Similarly, various intratumoral mechanisms, such as GBM-induced blood-brain barrier breakdown and glioma-immune cell interactions within the tumor microenvironment are also cited as contributing to network hyperexcitability. Substantial alterations to peri-tumoral glutamate and chloride transporter expressions, as well as widespread dysregulation of GABAergic signaling are known to confer increased epileptogenicity and excitotoxicity. The abnormal characteristics of GBM alter neuronal network function to result in metabolically vulnerable and hyperexcitable peri-tumoral tissue, properties the tumor then exploits to favor its own growth even post-resection. It is evident that there is a complex, dynamic interplay between GBM and epilepsy that promotes the progression of both pathologies. This interaction is only more complicated by the concomitant presence of spreading depolarization (SD). The spontaneous, high-frequency nature of GBM-associated epileptiform activity and SD-associated direct current (DC) shifts require technologies capable of recording brain signals over a wide bandwidth, presenting major challenges for comprehensive electrophysiological investigations. This review will initially provide a detailed examination of the underlying mechanisms that promote network hyperexcitability in GBM. We will then discuss how an investigation of these pathologies from a network level, and utilization of novel electrophysiological tools, will yield a more-effective, clinically-relevant understanding of GBM-related epileptogenesis. Further to this, we will evaluate the clinical relevance of current preclinical research and consider how future therapeutic advancements may impact the bidirectional relationship between GBM, SDs, and seizures.

show abstract

Section: From Laboratory To Clinical Translationmentioning

confidence: 99%

Section: From Laboratory To Clinical Translationmentioning

confidence: 99%

Section: The Importance Of Timingmentioning

confidence: 99%

Section: From Laboratory To Clinical Translationmentioning

confidence: 99%

See 2 more Smart Citations

Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

Hills

Kostarelos

Wykes

2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…The current oncological treatment of glioblastoma patients has been excellently reviewed elsewhere [ 129 ]. Although temozolomide might exert some anticonvulsant effects [ 130 ], here we will focus on pharmacological means of addressing glioma-associated seizures since there is an increasing understanding of the shared mechanisms of tumor progression and epileptogenicity, suggesting that certain compounds could establish novel strategies for the treatment of glioblastoma patients presenting epileptic seizures.…”

Section: Glutamatergic Mechanisms Of Glioma Progression and Tumor-associated Epilepsymentioning

confidence: 99%

Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy

Lange

Hörnschemeyer

Kirschstein

2021

Cells

View full text Add to dashboard Cite

The progression of glioblastomas is associated with a variety of neurological impairments, such as tumor-related epileptic seizures. Seizures are not only a common comorbidity of glioblastoma but often an initial clinical symptom of this cancer entity. Both, glioblastoma and tumor-associated epilepsy are closely linked to one another through several pathophysiological mechanisms, with the neurotransmitter glutamate playing a key role. Glutamate interacts with its ionotropic and metabotropic receptors to promote both tumor progression and excitotoxicity. In this review, based on its physiological functions, our current understanding of glutamate receptors and glutamatergic signaling will be discussed in detail. Furthermore, preclinical models to study glutamatergic interactions between glioma cells and the tumor-surrounding microenvironment will be presented. Finally, current studies addressing glutamate receptors in glioma and tumor-related epilepsy will be highlighted and future approaches to interfere with the glutamatergic network are discussed.

show abstract

Antiepileptic Strategies for Patients with Primary and Metastatic Brain Tumors

Newton,

Wojkowski

2024

Curr. Treat. Options in Oncol.

View full text Add to dashboard Cite

Opinion statementSeizure activity is common in patients with primary and metastatic brain tumors, affecting more than 50% of cases over the course of their disease. Several mechanisms contribute to brain tumor–related epilepsy (BTRE), including a pro-inflammatory environment, excessive secretion of glutamate and an increase in neuronal excitatory tone, reduction of GABAergic inhibitory activity, and an increase in 2-hydroxygluturate production in isocitrate dehydrogenase mutant tumors. After a verified seizure in a brain tumor patient, the consensus is that BTRE has developed, and it is necessary to initiate an antiepileptic drug (AED). It is not recommended to initiate AED prophylaxis. Second- and third-generation AEDs are the preferred options for initiation, due to a lack of hepatic enzyme induction and reduced likelihood for drug-drug interactions, especially in regard to neoplastic treatment. The efficacy of appropriate AEDs for patients with BTRE is fairly equivalent, although some data suggests that levetiracetam may be slightly more active in suppressing seizures than other AEDs. The consensus among most Neuro-Oncology providers is to initiate levetiracetam monotherapy after a first seizure in a brain tumor patient, as long as the patient does not have any psychiatric co-morbidities. If levetiracetam is not tolerated well or is ineffective, other appropriate initial AED options for monotherapy or as an add-on anticonvulsant include lacosamide, valproic acid, briviracetam, lamotrigine, and perampanel.

show abstract

Temozolomide and seizure outcomes in a randomized clinical trial of elderly glioblastoma patients

Cited by 16 publications

References 17 publications

Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy

Antiepileptic Strategies for Patients with Primary and Metastatic Brain Tumors

Contact Info

Product

Resources

About