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Epilepsy in Glioblastoma Patients: Basic Mechanisms and Current

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Epilepsy in Glioblastoma Patients: Basic Mechanisms and Current Review Review Epilepsy in glioblastoma Expert Review of Clinical Pharmacology patients: basic mechanisms © 2013 Expert Reviews Ltd and current problems in 10.1586/ECP.13.12 treatment 1751-2433 Expert Rev. Clin. Pharmacol. 6(3), 00–00 (2013) 1751-2441 Jordi Bruna*1,3, Júlia Glioblastoma-related epilepsy requires paying careful attention to a combination of factors Miró2 and Roser with an integrated approach. Major inter-related issues must be considered in the seizure care Velasco1,3 of glioblastoma patients. Seizure control frequently requires the administration of antiepileptic drugs simultaneously with other treatments, including surgery, radiotherapy and chemotherapy, 1Unit of Neuro-Oncology, Hospital Universitari de Bellvitge-ICO Duran i with complete seizure relief often being difficult to achieve. The pharmacological interactions Reynals, Barcelona, Spain between antiepileptic drugs and antineoplastic agents can modify the activity of both treatments, 2Unit of Epilepsy, Department of compromising their efficacy and increasing the probability of developing adverse events related Neurology, Hospital Universitari de to both therapies. This review summarizes the new pathophysiological pathways involved in Bellvitge and Cognition and Brain Plasticity Group (IDIBELL), Barcelona, the epileptogenesis of glioblastoma-related seizures and the interactions between antiepileptic Spain drugs and oncological treatment, paying special attention to its impact on survival and the 3Group of Neuroplasticity and current evidence of the antiepileptic treatment efficacy, including the potential usefulness of Regeneration, Institute of new third-generation compounds. Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, KEYWORDS: adverse events • antiepileptic drugs • chemotherapy • efficacy • epilepsy • glioblastoma • high-grade Bellaterra, Barcelona, Spain glioma • prophylaxis • seizures *Author for correspondence: Tel.: +34 932 607 711 Seizures are a common symptom in glioma disease, although in the large population stud- Fax: +34 932 607 882 patients. Approximately 20–40% of the adults ies, these figures are restrained to approximately with primary brain tumors experience one sei- 25% at initiation [2,5–10]. zure prior to the tumor diagnosis, and another Despite the high frequency of this symptom, 20–45% will suffer from seizures during the retrospective studies have shown suboptimal sei- course of the illness [1] . This incidence rate varies zure control in 9–46% of GBM patients, with depending on the tumor type, the grade of his- these treatment refractory patients presenting tological malignization and the tumor location. more than one seizure per month [2,6,7,11]. This AuthorSubsequently, tumors with a dysplastic Proof neuron fact highlights the importance of adequate inte- composition (e.g., dysembrioplastic neuroepithe- gration of epilepsy treatment in the complete lial tumors, gangliogliomas), have a very high therapeutic management of GBM patients. incidence rate at nearly 100%. Slow-growing Brain tumor-related seizures are focal in glial tumors are more frequently associated nature, although secondary generalization is not with epilepsy than high-grade glioma tumors uncommon and may happen quickly. Moreover, and intra-axial tumors with cortical involvement the risk of developing status epilepticus is not are more epileptogenic than extra-axial and deep negligible; patients with brain tumors comprise glial tumors, being insular, frontal and tempo- 4–12% of the total patients emerging with this ral locations more likely to present seizures at epileptic complication [10,12,13]. presentation or during the course of the disease An appropriate approach to the treatment of [2–4]. Specifically, overall incidence of seizures tumor-related epilepsy becomes important for in glioblastoma multiforme (GBM) patients, many reasons such as to decrease the morbid- without considering the location, has been ity associated with seizures [14], to reduce the reported between 25 and 50% at presentation risk of pharmacoresistent epilepsy [15] and to and another 20–30% during the course of the avoid any impairment in the patients’ quality www.expert-reviews.com 10.1586/ECP.13.12 © 2013 Expert Reviews Ltd ISSN 1751-2433 1 Review Bruna, Miró & Velasco of life [16] . Moreover, GBM patients and in general, brain tumor Considering the mechanism of action of most currently used patients, have special considerations, over and above the general AEDs, which block the Na+ and Ca2+ channels or enhance inhibi- non-neoplastic epileptic population, which need to be taken into tory mechanisms through an increase of GABAergic activity, only account in order to not only select the best treatment option for a few epileptogenic glioma pathways are involved by AEDs, which the tumor but also to reduce the therapeutic failures. might partially explain the failure of treatment in some GBM patients. Distinctive characteristics of GBM patients with epilepsy Pharmacokinetic considerations Several specific reasons have been identified that explain the inef- Around 40% of glioma cancer patients present low levels of AEDs ficacy and subsequent withdrawal of antiepileptic treatment in at the time of having a seizure [2,25–28]. This finding results, at GBM patients, which are not shared by other epileptic popula- least partially, from the fact that therapeutic AED levels in can- tions. These factors are mainly related with the pathophysiology cer patients are difficult to maintain because of pharmacoki- of brain tumor-related seizures, the consequences of pharma- netic interactions with concomitant administered medications, cokinetic drug interactions, the overexpression of multidrug- including chemotherapy and targeted cancer therapies. This transporter proteins in brain tumors, the progressive course of point becomes more relevant in GBM patients as the median the disease, the oncological treatments and the very often higher age of GBM patients at diagnosis is around 60 years with 25% of rate of adverse events induced by the antiepileptic drugs (AEDs) the patients being older than 70 years [29], a population segment in this population. usually under multiple medications. Pharmacokinetic interactions can alter the uptake, metabolism, Etiopathogeny of GBM-related seizures volume of drug distribution (due to competition in protein bind- The main mechanism considered to be involved in high-grade glial ing) and the clearance of administrated drugs. These complex tumor seizures is the imbalance between the inhibitory and excita- pharmacokinetic drug relationships, which are often difficult to tory brain neural networks caused by tissue and neural connectivity predict and control, can be associated with the following two damage. Additionally, other mechanisms at the molecular level main problems: the reduction of the antineoplastic agents and/or involving the tumor itself and host factors are emerging, which AEDs efficacy and the increase of toxicity related to both treat- could explain the different incidence rates between glioma types ments. As a result of these drug–drug interactions, the control of and histological grades, despite their location. tumor-related epilepsy, clinical assessment and patient survival These epileptogenic mechanisms comprise of changes in pH, can be compromised. neurotransmitters and ion levels, as well as in the expression of The activity of the cytochrome P450 system can be either voltage-dependent channels and receptors in tumoral and peritu- induced or inhibited by AEDs and corticosteroids. Enzyme- moral brain tissue [17,18]. Furthermore, observed expression of spe- inducing AEDs (EIAEDs) accelerate the metabolism of many cific glutamate receptors and glutamate transport impairment in chemotherapeutic drugs employed against GBM in several neoplastic glial cells may increase extracellular glutamate resulting trials, such as nitrosureas, irinotecan, taxanes, topotecan, thi- in a high excitability [19] . Moreover, the peritumoral tissue has also otepa, etoposide, vincristine, cyclophosphamide, temserolimus, been demonstrated to present an increased expression of NKCC1 imatinib, sorafenib, enzastaurin, vatalanib, tipifarnib, gefitinib and KCC2 voltage-gated ion channels that cause a perturbation and erlotinib [30–38]. EIAEDs can lead to a decrease of plasma in Cl homeostasis, which leads to a reduction in GABAergic levels when used with these agents, reducing their exposure and inhibition [20]. Furthermore, macro- or microhemorraging and potentially their effectiveness. However, the front-line antineo- edema related to the tumor increase the iron and decrease the plastic drug used to treat GBM, temozolomide, is a prodrug that magnesium and calcium levelsAuthor respectively, which may change undergoes Proof spontaneous conversion under physiological pH blood the membrane potential of neurons leading to spontaneous epi- conditions into the active alkylating agent, with minor hepatic leptiform discharge [18]. Moreover, changes in the expression of metabolism [39]. Therefore, no significant interaction should be aquaporin-4 found in GBM tumor cells facilitate the appearance expected between temozolomide and EIAEDs. Nevertheless, cau- of edema and seizures [21] . In addition, pH changes in intra- and tion must be taken with the prescription of AEDs associated to extracellular peritumoral tissue have been identified, making the metabolic acidosis, such as zonisamide and topiramate [40], due to tumoral and
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