Neuro-Oncology Practice

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1 Neuro-Oncology Practice Neuro-Oncology Practice 1(3), , 2014 doi: /nop/npu010 Time to focus on brain tumor-related epilepsy trials Paul Gallagher, John Paul Leach, and Robert Grant Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK (P.G., J.P.L.); Department of Clinical Neurosciences, Western General Hospital, Edinburgh, UK (R.G.) Corresponding Author: Robert Grant, MD, Department of Clinical Neurosciences, Western General Hospital, Crewe Road, Edinburgh, UK EH4 2XU Brain tumor-related epilepsy (BTRE) is a common complication of cerebral glioma. It has a serious impact on the patient s confidence and quality of life and can be life threatening. There are significant differences in the management of BTRE and nontumoral epilepsy in adults. Surgery is performed early in management, and resection can be curative. Radiotherapy can also improve seizure frequency. Antiepileptic drugs (AEDs) are started after first seizure but are only effective at stopping attacks in 50% of cases. There are no satisfactory randomized controlled clinical trials, or even good prospective series, to support using one AED over another with respect to efficacy. Guidelines are therefore based on poor levels of evidence. In general, the choice of AED may depend on risk of early side effect (rash, biochemical, or hematological effects) and whether drug interactions with chemotherapy are likely. In patients with suspected low-grade glioma, where use of chemotherapy early in the management is not standard practice and survival in measured in many years, the drug interactions are less relevant, and rational seizure management should focus on drugs with the fewest long-term effects on neurocognition, personality, mood, and fatigue. While intriguing and potentially very important, there is no good evidence that any specific AED has a clinical antitumor effect or improves survival. Development of special interest groups in BTRE within countries, or between countries, may be a model for promoting better BTRE trials in the future. Keywords: antiepileptic drug, drug-drug interactions, epilepsy, glioma. Seizures can result from any disruption of normal cortical activity and are therefore an expected complication of cerebral tumors. A tendency to recurrent unprovoked seizures is characteristic of epilepsy and requires treatment and specialist follow-up. Both primary and secondary brain tumors can cause seizures, although the former are significantly more epileptogenic and will be the focus of this review. Cerebral gliomas of all grades account for 28% of all brain tumors and have an incidence of 6 per100000peryear. 1 Data from the Central Brain Tumor Registry of the United States (CBTRUS), 1 collected between 2006 and 2010, suggest that the incidence of high-grade glioma (HGG) is more than 4 times that of low-grade tumors. While glioma is considered a rare tumor, using the RARECARE definition, 2 there will be new cases expected in North America and Europe annually. Over half of all patients with glioma develop seizures, 3 suggesting in excess of new cases of brain tumor-related epilepsy (BTRE) in these regions annually; if all primary and secondary cerebral tumors are considered, the figure is closer to Epileptic seizures have a significant impact on quality of life 4,5 and in themselves carry an intrinsic risk for harm, 6,7 especially when they are prolonged and generalized. For the nonspecialist, the changing nomenclature and terminology can be confusing, 8 but it is helpful and reasonable to maintain a pragmatic approach to classifying patients with BTRE, and these considerations are explored in this review. Seizures usually result in a symptomatic gain of function and positive phenomena that can be motor, sensory, or autonomic (oranycombinationofthese)dependingonthesiteofthelesion. Seizure type, frequency, and duration will determine how intrusive these episodes are on the patient s life and dictate the aggressiveness of management. The additional long-term deleterious effects of frequent seizures and their treatments on patient mood, cognition, personality, and energy levels can necessitate further pharmacological and nonpharmacological management strategies. These are compounded further in patients with BTRE who are suffering symptoms caused by the tumor itself, any required chemotherapy, and the side effects of antiepileptic drugs (AEDs). 4 There is a gulf of difference between low-grade glioma (LGG) and high-grade glioma in terms of symptoms, prognosis, treatments, and management priorities, 9 which will be highlighted throughout this article. In LGG, management can be focused on Received 3 March 2014 # The Author(s) Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please journals.permissions@oup.com. 123

2 symptoms such as seizures (initially, at least), whereas treatment of the tumor is paramount for high-grade lesions. This distinction informs an important variance in approach to these 2 patient groups and will be considered in the relevant sections. Despite brain tumors being a common cause of seizures with a potentially significant impact on the lives of patients already suffering effects of the primary lesion, the evidence for management of BTRE is far from robust. This article aims to review the current state of knowledge on BTRE, its management, and where further research is required. Identifying Patients at Risk of BTRE The risk of seizures occurring in patients with brain tumors depends on the location, cell type, grade, and size of the neoplasm. 10 Notably, most authors agree that presentation with epilepsy is a good prognostic feature with median survival of 3.5 years in patients without epilepsy and 6.9 years in those with epilepsy (HR, 0.52 [95% CI, ]; P ¼.0002), independent of type or grade of malignancy Some believe that the better survival may be due to earlier presentation and lead time bias ; however, it is also possible that cortically based tumors are more accessible surgically and are less likely to be associated with neurological impairment and disability. Tumors infiltrating the cortex and located in the frontal and temporal lobes, particularly the insular cortex, are most likely to cause seizures. 3,9 Seizures are most common in low-grade neuronal tumors and occur in up to 100% of patients with these lesions, as outlined in Table 1. While the risk of seizure is much higher with low-grade gliomas, the significantly higher incidence of high-grade disease means clinicians are most likely to see and treat seizures in this group. Interestingly, there is an inverse relationship between tumor grade and size (volume) and the incidence of seizures. 9 Smaller high-grade tumors tend to present with seizures, while the larger tumors present with symptoms potentially related to mass effect such as headache, cognitive deficits, or focal weakness; conversely, large low-grade tumors are more likely to present with seizures than those of less volume. The pathophysiology of this dichotomy is not well understood. Table 1. Incidence of seizures in differing tumor types Tumor Type Seizure Incidence DNET Up to 100% Oligodendroglioma* 89% 90% Ganglioglioma* 80% 90% Astrocytoma* 60% 75% Meningioma 29% 60% Glioblastoma multiforme** 29% 40% Metastasis 20% 35% Leptomeningeal tumor 10% 15% Primary CNS lymphoma 10% *Low-grade glioma, **High-grade glioma. (Adapted from Beaumont & Whittle et al./van Breeman & Vecht et al.) Causes of BTRE: Pathophysiology Epilepsy as a syndrome in general is classified as either focal or generalized, depending on whether seizures arise from a unilateral or bilateral hemispheric abnormality, respectively. 8 Brain tumors cause a localized cortical change, which results in focal unilateral seizures that may become more widespread: this is why epilepsy of focal onset can cause generalized seizures. Widespread abnormalities in neuronal physiology cause higher inherent epileptogenicity, resulting in an idiopathic generalized epilepsy (IGE) syndrome. These epilepsies, unless already existing prior to onset of the brain tumor, are distinct from BTRE and will not be dealt with further in this review. The biochemical mechanism of epileptogenicity arising from tumors remains unclear despite extensive research in this area since the last century. Indeed, understanding the mechanisms of BTRE may inform the wider study of epileptogenesis because there may be a number of common mechanisms with other epilepsies. There are likely to be a range of explanations, with dysfunction anywhere from the molecular level to that of the brain networks that propagate seizures. Of course, individual genetic factors will also contribute. Readers are directed to 2 reviews that are comprehensive, but the detail is beyond the scope of this text. 14,15 At the cellular level, neuronal tissue is thought to be fundamentally more epileptogenic than glial cells, although an astrocytic contribution to epileptogenesis has also been proposed. 16 This fundamental difference might explain the higher incidence of seizures in neuroepithelial and glial tumors compared with leptomeningeal neoplasia, for example (see Table 1). A higher density of voltage-gated ion channels within tumor cells 17 allows generation of action potentials, while downregulation of the predominant inhibitory GABAergic neurotransmitter receptors 18 may permit unwarranted excitatory events. Overall, it is likely there is an imbalance between the inhibitory GABAergic and excitatory glutamatergic systems, favoring excitation and resulting in unprovoked seizures and epileptogenesis. Indeed, there is evidence from animal studies to suggest that inhibition of glutamate release from glioma cells may be a therapeutic strategy for reducing seizure frequency. 19 The peritumoral tissue may be the harbinger of epileptogenesis, with changes in the histological structure and immunocytochemical profile of cells in this region. 20 Overexpression of gap junctions, which can propagate intercellular excitatory signals, have been demonstrated in LGGs and may further contribute to seizure generation. 21 A more alkaline ph in peritumoral cortex can also provide a more permissive environment for seizure production and spread. 14 At a macroscopic structural level, the concepts of denervation hypersensitivity, dysfunctional plasticity and secondary epileptogenesis have been proposed as potential epileptogenic mechanisms. 3,14 Denervation hypersensitivity describes the electrical isolation of a cortical region due to the infiltrating nearby lesion, which becomes hypersensitive to incoming stimuli and results in an exaggerated response that may then instigate network excitation. Plasticity is the repair mechanism of the central nervous system at the structural level whereby neural structures develop new functional capabilities to replace that of damaged tissue. Should this mechanism develop abnormally, the potential for aberrant signaling and connectivity is apparent. Secondary epileptogenesis 124 Neuro-Oncology Practice

3 implies that an actively discharging epileptogenic focus induces similar paroxysmal activity in regions that are distant to the original site. This theory is invoked for the minority of patients with BTRE, in which the epileptogenic focus does not correspond with the tumor location and is most commonly seen with temporal tumors. 22 Neurophysiologically, alterations in functional connectivity and local small world networks have been shown to be important in epileptogenesis in BTRE. 23 Management of BTRE Similarly to epilepsy in general, the diagnosis of BTRE is clinical and based on seizure semiology (what it looks like) and the experience reported by the patient (eg, auras). Patients with brain tumors are at a higher risk of epilepsy than the general population; therefore, the threshold for diagnostic doubt is arguably lower than in nontumor patients. Seizures will be of focal origin, but the distinction between whether the seizure remains unilateral (originating from the locale of epileptogenic lesion) or becomes bilateral (related to cortical spread from the initial epileptogenic focus) is important to evaluate overall risk of harm. Bilateral spread of the seizure is more likely to result in an impairment of awareness or loss of consciousness, while the site of the lesion will dictate the focal symptoms experienced. It follows then that seizures can lie on a spectrum from brief focal, unilateral sensory symptoms without impairment of awareness to prolonged bilateral motor involvement and loss of consciousness with a gradation of risk to the patient between these. Generalized seizures, in which patients lose consciousness and fall over, cause secondary injuries and limit daily activities, but equally frequent focal seizures can have a major functional impact on patients lives. 4 Prolonged generalized seizures increase the risk of hypoxic brain injury, which may be subtle but is cumulative over the years, and an impact on cognition from epilepsy in general has been reproducibly reported. 24 Sudden unexpected death in epilepsy describes fatality related to seizure in the absence of injurious cause. While overall incidence is low (,1/1000 patient years), prolonged, frequent and nocturnal generalized seizures significantly increase risk. 25 An important part of epilepsy management is to decide upon treatment based on a risk/benefit analysis of ongoing seizures versus the treatment options available. If the clinical history is in keeping with seizures, ancillary investigations, including EEG and imaging, may help determine etiology and inform prognosis. In patients with no focal cortical problem such as a brain tumor, treatment is usually withheld until a second seizure has occurred, unless there are inherent risks that are unacceptable to the patient or the likelihood of recurrence is high. After a second unprovoked seizure, however, the balance of risk favors treatment. 26 In the nontumor population, the majority of patients become seizure free on a single AED. Patients with BTRE, however, are at high risk of seizure recurrence after a single seizure, and therefore treatment should be commenced after the first event. 27 Additionally, patients with a causative lesion, such as tumor, are more often refractory to treatment. 28 EEG is not likely to be required when a lesion is identified in a clearly focal-onset syndrome. When a brain tumor is found but no seizures have occurred, prophylaxis with AEDs is not advised presently, following extensive review of the available literature. 29 However, a Cochrane Review 30 from 2008 addressing this question raised concerns about the quality of current evidence upon which to base conclusions and suggested that further trials are needed to provide more definitive advice, particularly since most studies were based on older AEDs and the altered risk/benefit ratio in using newer AEDs may challenge current recommendations in the future. This is relevant from the perioperative to the terminal stages of disease, and studies are required to address both of these periods in particular. AED use is usually based on the phrase start low, go slow with AEDs initiated at a low dose with a slow subsequent titration, when possible, to minimize side effects and maximize concordance with the aim of seizure freedom and no associated side effects. The former aim may be more difficult to attain in BTRE, in which refractory seizures are more common as exemplified by a large prospective observational study of patients with BTRE. Seizures were predominantly related to LGG, and 61% (111/183) did not achieve adequate control with first-line AEDs, of which valproate, carbamazepine and gabapentin were most commonly used. 31 A significant finding was that the frequency of generalized seizures reduced with glioma and seizure treatment, yet 74.2% had persistent focal seizures during follow-up, particularly in lowgrade gliomas. There was an initially limited range of AEDs in the 1960s and 1970s, but an explosion in the number of AEDs since the 1990s has left us with more than 20 to choose from currently. There remains a distinction, however, between older AEDs and newer AEDs, both in terms of their time of discovery and clinical use as well as their pharmacokinetic properties and side-effect profiles. Newer AEDs generally have fewer drug-drug interactions than older ones, resulting in a clinically useful further subcategorization of AEDs as either enzyme-inducing (EIAEDs), nonenzyme-inducing, or enzyme-inhibiting with reference to their effect on the hepatic cytochrome P450 metabolic pathways. This is particularly relevant to BTRE, in which the antineoplastic treatments may undergo hepatic metabolism and lead to potential interactions as outlined in Table 2. Additionally, the tolerability of newer AEDs is generally more favorable, as discussed further below. In choosing AED monotherapy, one must consider specific patient factors including sex, age, other treatments, and comorbidities. 32 Additionally, the tumor grade in patients with BTRE will influence planned treatments and should be a factor influencing AED choice. Choice of AED monotherapy in BTRE does not have a good evidence base. Despite the high incidence of glioma-related epilepsy, there are surprisingly few good quality studies to recommend any particular antiepileptic drug over another. Indeed, a recent Cochrane Systematic Review of the literature failed to identify any randomized phase III studies of antiepileptic drugs in glioma, 33 although one small randomized safety and feasibility phase II pilot study was identified that examined postoperative switch of phenytoin to levetiracetam and suggested that it was safe to do following craniotomy for supratentorial glioma. 34 Evidence Underlying AED Choice in BTRE Good evidence for the choice of AED in BTRE will remain scarce as long as AED marketing trials exclude patients with a progressive structural brain lesion. While this exclusion criterion makes sense Neuro-Oncology Practice 125

4 Table 2. Effects on serum concentrations of concomitant antiepileptic drug and chemotherapy use* AED Concomitant Use Effects AED Effects Chemotherapy Effects Increase AED Levels ( toxicity) Reduce AED Levels ( efficacy) Increased Chemotherapy Levels ( toxicity) Reduced Chemotherapy Levels ( efficacy) Phenytoin Dexamethasone Nitrosureas Methotrexate 5-FU Carmustine Vincristine Cisplatin Methotrexate Carbamazepine Cisplatin Valproate Methotrexate Nitrosureas Cisplatin Cisplatin *Adapted from Vecht CJ, Wagner GL, Wilms EB. Interactions between antiepileptic and chemotherapeutic drugs. Lancet Neurology2003; 2(7): Abbreviations: AED, antiepileptic drugs; 5-FU, 5-fluorouracil. in ensuring that a potential new AED does not have its efficacy undermined by especially refractory patients, it does mean that there is a need for specifically designed trials of AED monotherapy for BTRE. So far, there has been no coherent grouping of neurologists/neuro-oncologists with an interest in AED trials in Europe or North America. Organizations such as the European Organization for Research Trials Collaboration (EORTC), National Cancer Institute (NCI), or National Cancer Research Institute (NCRI) have historically focused on tumor-directed studies rather than symptom control or quality-of-life research. As a result, there has been no real progress in the field of BTRE over the past 20 years. There are not even any large prospective comparator epilepsy studies of efficacy of AEDs with different modes of action and side-effect profiles. We would argue that control of symptoms (including seizures) and quality-of-life research are of particular importance to patients, especially given their increasing survival effected by current treatment strategies. Most of the evidence comes from single-center retrospective or unblended prospective studies, often treating historical or poorly matched comparators with variable doses of older AEDs known to have a high frequency of side effects (phenobarbitone, phenytoin). The current literature on the effectiveness of specific AEDs in glioma-associated epilepsy is confounded by the fact that all are open label studies without satisfactory controls and each study having several important potential biases: Retrospective series 32,39 42 Small numbers Co-intervention of surgery, radiotherapy or chemotherapy 43 Addition of second-line AED to existing AED 29,31,33 Short follow-up periods 29,33,34,38,40 Poor documentation of seizure frequency at study entry 38 Dropouts from the study 37 Different tumor types or grades within the study 33,44 Poor prospective documentation of short and longer term side effects (all) Poorly matched comparator groups, often with known poor side effect profiles 45 Differences Between Management of Epilepsy in General and BTRE Following a first seizure in adults without a brain tumor, there is no good evidence for commencing long-term AED treatment: 23 Any benefit in reducing seizure recurrence is short-lived, and the possibility of side effects puts the balance in favor of deferring AED treatment until a second seizure has occurred. In patients with BTRE, however, the likelihood of a second seizure without treatment is high enough such that intervention with AEDs is recommended. 24 Additionally, the MESS trial 44 showed that seizure frequency was reduced for the first 1 2 years with AED commencement. When survival is likely to be limited by a HGG, such a difference may be significant and may inform the patient s choice of AED. In glioma-related epilepsy, 60% 80% of patients with gliomarelated epilepsy will undergo surgery early, which contrasts sharply with surgery rates for patients with epilepsy without associated brain tumors. Adequate tumor resection is the most important predictor for seizure control and significantly improves the likelihood of remaining seizure-free postoperatively. However, even with intraoperative MRI-guided surgery, total resection is achieved in no more than 36% of patients with lowgrade glioma. 50 Seizure control rates are up to 80% 90% when epilepsy-directed tumor surgery is planned and assessed with combinations of EEG, Magneto-encephalogram, functional MRI, and AED therapy. 42,51,52 The resection in HGG is not for seizure control specifically, but those who have had a complete resection are more likely to remain seizure free for a year. There may be a case for AED withdrawal, especially when AED side effects are present. Paradoxically, however, patients whose epilepsy is drug resistant and of long duration appear to have better survival than those in which epilepsy is drug responsive. 53 Side effects of AEDs are more frequent in patients with brain tumors compared with the overall population with epilepsy. Severe hypersensitivity skin reactions, such as Stevens-Johnson syndrome, have been reported in patients who received cranial radiotherapy while taking phenytoin and carbamazepine, 54,55 and the frequency of mild skin rashes in patients with brain 126 Neuro-Oncology Practice

5 tumors is about twice that for patients on AEDs who do not have a tumor. 56,57 The reason for this remains obscure. More easily explained are other side effects, for example, when patients already have impaired cognitive function or suffer fatigue from concomitant radiotherapy or chemotherapy. The range of concomitant treatments given to those with BTRE greatly increases the likelihood of drug-drug interactions. Use of dexamethasone, proton pump inhibitors, and chemotherapy may interact with AED pharmacokinetics. Other treatments that are effective at reducing seizure frequency are also often given at the same time an AED is started. Radiotherapy and chemotherapy 61,62 can significantly reduce the epileptogenic potential of the lesion. This effect of chemotherapy on improving seizure control appears to be unrelated to treatment of the mass effect because it seems to be as effective in infiltrating LGG as massforming HGG. The extent of resection, radiotherapy, and chemotherapy may all confound direct comparison of AED studies in BTRE. There is a higher likelihood of late AED adverse effects such as of fatigue, cognitive, behavioral, sleep, and mood effects in BTRE patients as compared with nontumor-related epilepsy patients. This may relate to other local effects on brain structure from the tumor, surgery, radiotherapy, and/or chemotherapy. A recent study of clinically stable brain tumor patients attending a neurooncology clinic following treatment demonstrated that fatigue was a concern in 64%, memory in 58%, concentration in 57%, mood in 47%, sleep in 40%, and anger and irritability in 38% of cases. 63 Although AEDs may not be the sole cause of these side effects, they are likely to be a contributing factor since high levels of these symptoms have been documented in the labels for the specific AEDs themselves. Patients with HGG have a drastically reduced life expectancy compared with nontumor patients and will succumb to the primary condition in the majority of cases. This reinforces the desire to maintain quality of life, perhaps with more urgency than in the nontumor population. Fig. 1. Suggested approach to treatment of BTRE: general measures. LG versus HGG-related Epilepsy Brain tumor-related epilepsy should be approached quite differently in patients with low- and high-grade disease. There are differences in demographics, presentation, seizure type, urgency of treatment, and concomitant drug use between these patients, and these factors must inform their holistic management. Such differences may potentially mandate or allow consideration of different treatment approaches, and these are summarized in Figs LGG-associated Epilepsy Low-grade glioma is often managed expectantly with a watch and scan policy, and treatment is focused on symptom management. It can be considered similar to focal epilepsy in the general population when surgical excision of the epileptogenic lesion may only be considered if seizures are refractory to medical management and are having a significant impact on the patient s life. Patients are more likely to be young (aged years) and suffer with focal seizures alone, although they may present with generalized seizures during the course of their illness. 26 Life expectancy Fig. 2. Suggested approach to treatment of BTRE: LGG/younger patients. Fig. 3. Suggested approach to treatment of BTRE: older/hgg patients. Neuro-Oncology Practice 127

6 is measured in years for these patients, with follow-up studies showing a median survival of more than 16 years for patients with oligodendrogliomas and mixed glioma cell types. 64 It is therefore a somewhat chronic condition, but the specter of transformation to a high-grade tumor remains and no doubt adds to the complexity of the psychological impact of an already unpredictable course for patients. That said, the priorities of seizure management are similar to those for nontumor epilepsy in a younger cohort. 1 Thus, long-term side effects of medications, teratogenicity, fertility, breast-feeding, occupational, and driving considerations must be acknowledged. In addition, most patients with LGG have epilepsy as their only symptom, and clinically relevant focal weakness, significant cognitive problems, and headaches are unusual. Surgery can be planned or deferred if a watch and scan policy is considered. Treatment with early radiotherapy or chemotherapy has not been shown to extend survival. This allows neurologists to play a major role in patient management, in collaboration with oncologists. Since dexamethasone, proton pump inhibitors, H2 receptor antagonists, and chemotherapy are usually not required, the hypothetical issue about clinical relevance of enzyme-inducing AEDs resulting in poorer response or survival is not as important. The seizures in patients with low-grade glioma may be somewhat akin to focal seizures in those without a mass lesion. The focus can therefore be on the most effective drug for focal epilepsy with the lowest adverse-event profile. The emphasis in the European Federation of Neurological Sciences and European Association for Neuro-Oncology guidelines on low-grade glioma 24 focuses on the potential importance of AEDs and their interactions with chemotherapy and targeted therapies that might be required in the future. This issue is particularly important for patients treated with enzyme-inducing AEDs (eg, phenobarbitone, phenytoin, and carbamazepine) or enzyme-inhibiting AEDs (eg, valproate), especially when the chemotherapy is also metabolized via the cytochrome P450 system. A recent International League Against Epilepsy (ILAE) review shows that levetiracetam and zonisamide join carbamazepine and phenytoin with level A efficacy/effectiveness evidence as initial monotherapy for adults with focal onset seizures. 65 HGG-associated Epilepsy Reviews in elderly patients with nontumor-associated epilepsy support the use of lamotrigine as being the most effective medication as measured by 12-month retention and seizure-freedom rates, with levetiracetam being a close second. 66 Since there is no hard evidence of differential efficacy of AEDs, the three main issues around prescription of AEDs for patients with HGG are tolerability, drug-drug interactions with current or future concomitant treatment, and the potential effect of AED on tumor biology (ie, do some AEDs have a clinically relevant antitumor effect?). Of course, some of these issues also apply to LGG patients with BTRE but are perhaps more relevant to the HGG patient group. HGG-associated Epilepsy: Tolerability of AEDs The adverse-event profiles of AEDs in small studies are not systematically reported, which makes interstudy comparisons impossible between larger trials or older cohorts. Some side effects are likely to be similar, regardless of the cause for epilepsy; however, there are reports suggesting that some side effects are more common in BTRE, as above. The most consistently reported early side effects are similar to those in nontumoral studies, namely rash, hematological toxicity, hepatic dysfunction, and neurological symptoms. Rash occurs more commonly with enzyme-inducing AEDs (4% 6% with phenytoin, carbamazepine, and lamotrigine compared with,1% with levetiracetam, valproate, gabapentin, topiramate, and vigabatrin). 67 Rash is more likely if drugs are introduced quickly, which can be a problem when then is a desire to load the medication more quickly before neurosurgery. In this situation, antiepileptics such as levetiracetam and valproate may be preferred over lamotrigine. Although allergic rash usually presents early, sometimes rash can be masked by concomitant steroids and only becomes apparent when steroids are reduced or discontinued. Hematological disorders, especially leucopenia and thrombocytopenia (eg, with carbamazepine, valproate, and phenytoin) may lead to difficulties if chemotherapy is begun shortly after introduction of the antiepileptic, leading to confusion about whether the AED or the chemotherapy caused the hematological disorder. Hepatic disturbances are seen with valproate, carbamazepine, and phenytoin. There is general agreement that the newer antiepileptic drugs have fewer early side effects than the older agents. However, many of the newer AEDs are associated with significant sideeffect profiles, requiring withdrawal of agents in many studies, but these tend not to be rash or early side effects. Late side effects commonly include fatigue, psychosis, behavioral symptoms, depression, and disabling cognitive complications. Psychiatric side effects are less common with lamotrigine, gabapentin, oxcarbazepine, and vigabatrin compared with levetiracetam, topiramate and zonisamide. 68 Headaches and worsening of seizures are not uncommon with AEDs and can be alarming for the patient and clinician, often requiring exclusion of imaging progression. Topiramate specifically can cause acute visual deterioration and renal stones in addition to high frequencies of psychosis. Vigabatrin is rarely used now because of irreversible visual field defects and the requirement for frequent visual field assessment. Lacosamide may cause cardiac conduction defects, and EKGs are suggested before dosage increases. HGG-associated Epilepsy: Drug-drug Interactions Drug interactions can be pharmacokinetic (affecting absorption, metabolism, or excretion) or pharmacodynamic (causing agonism or antagonism between the drugs in question). Given the differing end-organ mechanisms of actions of chemotherapy and antiepileptic drugs, pharmacodynamic interactions are not usually clinically relevant, if present at all, and will not be discussed here. Important pharmacokinetic interactions are usually related to hepatic metabolism, specifically the cytochrome P450 enzymatic metabolic pathway that processes most drugs. The main risk of these interactions is reduced efficacy or increased toxicity of the 128 Neuro-Oncology Practice

7 coadministered medications; some examples are outlined in Table 2. With regard to glioma, chemotherapeutic options are relatively limited in comparison with AED options. Thus, considering AEDs with the least risk of interaction with PCV (procarbazine, CCNU, vincristine) or temozolomide would be appropriate in the first instance. Importantly, dexamethasone and omeprazole are CYP substrates, with enzyme-inducing AEDs known to reduce the effectiveness of glucocorticoids. Procarbazine, nitrosoureas and vincristine are CYP3A4 substrates, amongst others, as are carbamazepine, clobazam, phenobarbital and zonisamide leading to potential competitive metabolism and interactions, but the clinical relevance of this in practice is not known. Temozolomide is spontaneously hydrolyzed at physiologic ph to its active metabolites (MTIC, AIC, and methylhydrazine), which means no hepatic metabolism is required. However, it is known to induce CYP3A4, and concomitant valproate use reduces its clearance by about 5%. This may account for the higher incidence of hematological toxicity when the 2 medications are given concurrently in glioblastoma. 69 Newer AEDs have fewer interactions than older ones and are generally preferred from a drug-interaction viewpoint. Lamotrigine, levetiracetam, and temozolomide are substrates for the multidrug resistance gene (MDR1) product P-glycoprotein (P-gp), however, 70 and actively transport such substrates from cells. Tumor cells have higher expression of MDR proteins (high grade more so than low grade), which may explain some of their pharmacoresistance to AEDs or temozolomide. 71 Patients with glioblastoma and seizures are generally older and take other concomitant medications, similar to epilepsy in the elderly in general. Their drug tolerability is generally less, and neurocognitive effects are more frequent, especially after resection and radiotherapy. Age-related physiological changes, comorbidities, comedications, cognition, falls risk, and side-effect tolerance must all be considered in AED choice for the elderly. That said, lower doses of AEDs can be used, and generally the treatment outcome is better in elderly patients. Similarly, in patients planning to have chemotherapy. For this reason, newer AEDs are preferred, given their lack of pharmacological interactions and their proven efficacy in the general epilepsy population. A randomized trial of selected epilepsy treatments, including only patients older than age 60 years, 77 showed that the retention rate of lamotrigine was significantly better than that of carbamazepine. This was reproduced in a subsequent multicenter randomized trial 78 that showed similar efficacy between lamotrigine and carbamazepine (52% vs 57% free of seizures in the last 20 weeks of a 40-week study period, respectively), but again retention was better with lamotrigine (14% vs 25% discontinued treatment because of unwanted side effects). Reliable evidence supporting the clinical effect these drugdrug interactions (eg, AEDs, dexamethasone, proton pump inhibitors) with common chemotherapies used in treatment of gliomas (temozolomide, nitrosoureas, procarbazine) is very limited. The main difficulty is that we do not know the effective chemotherapy dose range for treating glioblastoma. Indeed, we do not routinely check chemotherapy levels, but instead we look at how many courses of chemotherapy can be tolerated without myelosuppression, hepatic toxicity, or lung toxicity. We do know that there are interactions between valproate (an enzyme inhibitor) and nitrosourea-based chemotherapy 79 as well as valproate and temozolomide through a different mechanism of acting as an inhibitor of histone deacetylase. 80 In a retrospective study, Oberndorfer et al. found an association between improved survival in patients with glioblastoma who were receiving valproate during nitrosourea-based chemotherapy compared with those receiving enzyme-inducing AEDs. 67 Valproate was also associated with increased hematotoxicity. Do AEDs Have an Antitumor Effect? Some AEDs have been shown to have an antitumor effect in the laboratory including valproate, carbamazepine, 84,85 and phenytoin, 86 while levetiracetam may enhance the response of glioblastoma to temozolomide. 87,88 None, however, have been used specifically for an antitumor effect in glioma. A subgroup analysis of the EORTC/NCIC trial of concomitant and adjuvant temozolomide plus radiotherapy versus radiotherapy in patients with malignant glioma suggested that those taking valproate and temozolomide concomitantly had a better survival. 68 Interestingly, this analysis showed no difference in survival in the direct analysis between valproate versus those treated with enzyme-inducing AEDs in the study. It was only when there was a subgroup analysis dividing patients further into chemo-radiotherapy and radiotherapy that there appeared to be a significant survival benefit for those taking valproate in the chemo-radiotherapy group. Paradoxically, there was a trend to worse outcome in those taking valproate in the radiotherapy-alone group of that study; therefore, it is doubtful that valproate alone was the explanation. If there is an effect, it may be due to the valproate increasing the temozolomide blood levels. Those who took valproate had more hematological toxicity, with requirement to dose-reduce chemotherapy and fewer courses. A recent study 69 again suggested improved survival with valproate: this retrospective analysis 544 patients, where 403 were taking AEDs 217 had seizures before radiotherapy, only 29 were taking valproate. This survival effect has not been replicated in the analysis of the large MRC BR12 randomized controlled trial of temozolomide versus PCV chemotherapy in recurrent malignant glioma. 89 Targeted chemotherapies have been shown to be interact with AEDs in some studies. EIAEDs resulted in significant peaks and troughs in concentrations of tipifarnib, a farnesyltransferase (FTase) inhibitor, in patients with recurrent glioblastoma. However, the drug levels were sufficient to inhibit FTase even in the presence of EIAEDs; therefore, the clinical relevance is uncertain. 90 In a similar study of imatinib and (CYP3A4) EIAEDs, mean trough levels of the chemotherapy were reduced compared with those taking non-eiaeds or those not taking AEDs. 91 In an earlier study, 92 surprisingly, patients on EIAEDs had improved progression-free survival. Late Effects From Antiepileptic Drugs Trying to disentangle the effect of AEDs from other tumor and treatment-related comorbidities (fatigue, cognitive problems, mood, behavior) requires focused history-taking to establish the onset of symptoms and determine whether they may be Neuro-Oncology Practice 129

8 associated with introduction of an AED (idiosyncratic), incremental doses of AEDs (potential toxicity), or addition of a second AED (polypharmacy). It is methodologically difficult to compare AEDs in their likely frequency of causing fatigue or other adverse events because there is no clear standardization of definition or severity of the symptom (fatigue, tiredness, sleepiness) or reporting frequency between studies. Frequencies vary depending on the population under study (pain, migraine, psychiatry, epilepsy), and doses vary from study to study. Two particularly frequent concerns of patients attending outpatient neuro-oncology clinics are fatigue and memory problems. Fatigue is defined as abnormal tiredness that may vary in severity and pattern, does not improve with sleep, and negatively interferes with daily functioning. It can be a major contributor to the symptomatology of patients with a brain tumor Fatigue early in the treatment process can be related to anxiety about diagnosis or pending treatments, depression, physical fatigue (eg, with hemiparesis), drugs, (eg, AEDs), anxiolytics, or dexamethasone-related sleep disturbance. Later in the treatment process, radiotherapy and chemotherapy may be additional factors in fatigue; this may be direct (eg, late pituitary gland underactivity due to radiotherapy) or indirect (eg, associated with anemia). Fatigue has been commonly associated with AEDs in placebo-controlled randomized controlled trials of nontumorrelated epilepsy and with phenobarbitone, phenytoin, carbamazepine and valproate as well as the newer AEDs when used for other indications and compared with placebo (eg, neuropathic pain, headache, psychiatric disorders). When these agents have been used in add-on epilepsy trials, one might expect a higher frequency of fatigue because of the combination of AEDs. If fatigue is severe, consideration should be given to trying monotherapy AED, reducing the AED dosage, changing AEDs (where there is a temporal relationship to increasing fatigue and seizures are continuing), or stopping AEDs completely. Discontinuation is certainly reasonable when the patient has had a tumor resection and there has been a stable period with no seizures since surgery. Cognitive problems are also common for brain tumor patients at diagnosis and after treatment. 82 Reasons are multiple, and there is much overlap with identified causes of fatigue. Studies in nontumor patients report higher frequencies of attention, memory, and executive problems in epilepsy cohorts taking AEDs. Factors affecting cognition include uncontrolled generalized epilepsy and, in many studies, polypharmacy, 4,5 which stresses the importance of choosing the right drug at the right dose while avoiding polypharmacy whenever possible. In patients with low-grade glioma, statistically significant deficits in domains of attention, executive function, and information processing have been found in comparison with healthy controls. 4 Patients with glioma had lower levels of cognitive functioning and healthrelated quality of life (HRQOL) scores than healthy controls, and a higher epilepsy burden was associated with even more severe cognitive deterioration, suggesting that seizures (or their treatments) have an independent negative impact. Despite this, there was no significant difference in physical function (as measured by the Karnofsky performance score) or their ability to manage activities of daily living (Barthel ADL Index), although the authors admit the limitations of such indices in this group. Patients using AEDs performed worse in all cognitive domains, except for verbal memory, compared with those not using AEDs in this study. Notably, the HRQOL of glioma patients was equivalent to that of epilepsy patients without glioma. 96 Deficits are twice as common in those who have had radiotherapy than in those with low-grade glioma who have not yet been treated with radiotherapy. Although a fraction dose of, at most, 2Gy is considered safe, total safety is not possible. 4,5,97 Seizures have a negative impact on cognitive function and quality of life in glioma patient similar to that of the general epilepsy population. 4 Although cognitive deficits in this patient group are likely multifactorial, 5 there is no doubt that good seizure control is at the heart of treatment. Conclusion In summary, patients with brain tumors have a high risk for developing seizures, but their management may differ significantly from those with epilepsy without underlying tumors. The epilepsy is often refractory to AEDs but can improve with tumor-directed therapies including surgical resection, radiotherapy, and chemotherapy. There have been no phase III randomized controlled trials or well-conducted clinically controlled prospective studies to determine the most efficacious antiseizure treatment strategy. There is a strong case for separating anti-btre studies into those with low-grade glioma and those with high-grade glioma/ glioblastoma because the treatment questions may be different. In low-grade glioma, issues of efficacy and long-term side-effect profile, especially for fatigue and cognition, will be most important. In high-grade gliomas, the issues focus on the clinical importance of potential drug-drug interactions and any potential antitumor effect from the addition of specific AEDs to standard chemotherapy. In the terminal phase of illness, in which 10% 15% of patients will develop new epilepsy in the last 3 months of life or lose of control of seizures secondary to problems with dysphagia or drowsiness, the questions may focus on the route by which antiepileptic preparations can be given most appropriately (eg, subcutaneous, buccal, long-acting oral preparations). AED trials in BTRE will, without a doubt, require a coordinated team approach involving neurologists in collaboration with neurooncologists. Knowledge of the potential AED profile of the individual drugs and their potential short- and long-term side effects, especially cognition, are in the realm of neurology and neuropsychology, rather than oncology, and extend the role of and need for multidisciplinary team care beyond that of reviewing scans for progression or response and advising on primary tumor treatment options. The best mechanisms for running large multicenter trials in BTRE need to be explored. It may be that the best trial centers to coordinate low-grade glioma studies are the existing epilepsy trials networks (eg, MRC), while high-grade glioma epilepsy trials may best coordinated by the cancer trials units (eg, EORTC, NCI). In the United Kingdom, a tumor-associated epilepsy interest group has been established at 12 interested centers, and discussions have opened to add a BTRE arm to an existing phase IV (postlicensing) study. Serious discussion about setting up specific AED studies in BTRE needs to start soon, or epilepsy care in neurooncology clinics will be no further ahead 10 years from now. As the treatment of epilepsy care has moved forward, it would be a tragedy if patients with an underlying brain tumor were denied the same improvement in quality of life, no matter how long the survival opportunity. 130 Neuro-Oncology Practice

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