Seizure prognosis in brain tumors: new insights and evidence-based management.

Brain tumor-related epilepsy (BTE) is common in low- and high-grade gliomas. The risk of seizures varies between 60% and 100% among low-grade gliomas and between 40% and 60% in glioblastomas. The presence of seizures in patients with brain tumors implies favorable and unfavorable factors. New-onset seizures represent an early warning sign for the presence of a brain tumor and count as a good prognostic factor for survival. Recurrence or worsening of seizures during the course of disease may signal tumor progression. Each of the modalities for tumor control (i.e., surgery, radiotherapy, chemotherapy) contributes to seizure control. Nevertheless, one third of BTE shows pharmacoresistance to antiepileptic drugs (AEDs) and may severely impair the burden of living with a brain tumor. For symptomatic therapy of BTE, seizure type and individual patient factors determine the appropriate AED. Randomized controlled trials in partial epilepsy in adults to which type BTE belongs and additional studies in gliomas indicate that levetiracetam is the agent of choice, followed by valproic acid (VPA). In the case of recurring seizures, combining these two drugs (polytherapy) seems effective and possibly synergistic. If either one is not effective or not well tolerated, lacosamide, lamotrigine, or zonisamide are additional options. A new and exciting insight is the potential contribution of VPA to prolonged survival, particularly in glioblastomas. A practice guideline on symptomatic medical management including dose schedules of AEDs is supplied.

Tumour and surgery effects on cognitive functioning in high-grade glioma patients.

BACKGROUND: Many high-grade glioma (HGG) patients have cognitive impairments, which impact daily functioning. Cognitive impairments can be caused by tumour-, treatment-, and patient-related factors. The effect of the tumour and of surgical resection on cognition is, however, not well known. We investigated tumour and surgical effects on cognitive functioning in patients with HGG. METHODS: At baseline, preceding surgery, 62 patients with HGG underwent neuropsychological testing concerning seven cognitive domains: verbal and working memory, attention, executive functioning, psychomotor function, information processing speed, and visuoconstructive abilities. Thirty-nine patients were included in follow-up testing after surgery, but before subsequent treatment. Tumour size and site, use of anti-epileptic drugs and corticosteroids, and extent of resection were recorded. RESULTS: Compared to healthy controls, cognitive functioning of patients was significantly impaired in all domains. Prior to surgery 79 % (49 of 62) of patients had cognitive impairment in at least one domain. At median follow-up of 5 weeks after surgery, 59 % (23 of 39) of patients were cognitively impaired in at least one domain. At follow-up, 49 % showed improvement, while 23 % declined. Left hemisphere tumour localization was associated with worse verbal memory (P=0.004), and larger tumours in this hemisphere with poorer executive functioning (P < 0.001). Changes in cognitive performance at follow-up relative to baseline were not related to tumour characteristics or extent of resection. CONCLUSIONS: Tumour-related cognitive deficits are present in a majority of HGG patients preceding surgery. Surgery does not result in cognitive deterioration in the short term in most patients.

Seizure characteristics and prognostic factors of gliomas.

Epilepsy in neuroepithelial tumors is highly prevalent. Neurogliomas (dysembryoplastic neuroepitheliomas [DNETs] and gangliogliomas) have a seizure incidence of 80-100%, low-grade gliomas of 60-85%, and glioblastoma of 30-60%. With each type, the appearance of seizures is usually the presenting clinical symptom, and with neuroglial tumors often the only clinical sign. Tumor locations in the temporal and insular cortex are associated with a higher risk of developing epilepsy in both neuroglial tumors and low-grade gliomas. Focal seizures with or without alteration of consciousness and/or secondary generalization are common. Focal seizures with altered consciousness are present in 50-70% of neuroglial tumors, and secondarily generalized seizures in 70% of low-grade gliomas. Surgical treatment, particularly gross tumor resection, contributes strongly to seizure freedom, especially in neuroglial tumors. Refractory epilepsy is more common in low-grade gliomas, occurring in 30-35%. Recurrence or worsening of seizures is often associated with tumor recurrence in glioblastomas. Translational studies have revealed a strong prevalence of IDH1 enzyme mutation together with the presence of seizures and long-term survival in low-grade gliomas. Disturbances of glutamate metabolism occur both in low-grade tumors and glioblastomas, and provide insight into mutual cellular pathway abnormalities contributing to both seizure development and tumor growth. Likewise, the recent clinical observations on antitumor activity of the anticonvulsant valproic acid in glioblastoma now provide promising outlooks on single therapies that target both seizures and gliomas.

Enzyme induction with antiepileptic drugs: cause for concern?

Several commonly prescribed antiepileptic drugs (AEDs)-including phenobarbital, phenytoin, and carbamazepine-stimulate the synthesis of a broad range of monooxygenase and conjugating enzymes. These agents are well known to reduce the duration and action of many lipid- and non-lipid-soluble drugs, including anticoagulants, cytotoxics, analgesics, antiretrovirals, glucocorticoids, statins, antihypertensives, oral contraceptives, psychoactive drugs, immunosuppressants, and of course, other AEDs. This process, therefore, may be associated with a number of clinical problems including higher cancer mortality, progressive AIDS, transplant rejection, and unwanted pregnancy. Withdrawal of enzyme-inducing AEDs will increase the concentration of induced drugs, bringing with it substantial risk of toxicity if doses are not concomitantly reduced. Yet the potential widespread adverse health consequences of these interactions, both with AED initiation and withdrawal, remain largely underappreciated. Furthermore, induction also affects enzymes involved in endogenous metabolic pathways, and can alter bone biochemistry, gonadal steroids, and lipid markers. Therefore, enzyme-inducing AEDs may contribute to the development of a number of comorbidities, including osteoporosis, sexual dysfunction, and vascular disease. This process continues as long as the patient takes the inducer. Modern AEDs that do not possess this property have similar efficacy for the common epilepsies. Accordingly, perhaps consideration should be given to starting treatment with, or even switching patients to, non-enzyme-inducing AEDs.

Pregnancy in women with gliomas: a case-series and review of the literature.

The occurrence of pregnancy in women with brain tumors confronts both patients and physicians with difficult decision making at each stage of pregnancy. We studied the course of events of nine pregnancies in seven women with low-grade glioma in our hospital over a 10 year period. Five patients had a surgical resection, one a biopsy and one woman was followed by wait-and-see policy before pregnancy. In two women, a therapeutic abortion was carried out in the first trimester because of signs of progression, necessitating surgical removal of the tumor. In the other five women pregnancy had an uncomplicated course. Based on a literature review, we found 28 women diagnosed with a known glioma before becoming pregnant. All pregnancies but one, were uneventful and all women had a normal delivery, including the seven cases with exposure to chemotherapy and in whom healthy babies were born. A total of 75 pregnant women were identified in whom new onset glioma developed, which was high-grade in 56 %, and becoming symptomatic in 51 % during the third trimester, usually by focal neurological deficits. We conclude that in relation to pregnancy, low-grade gliomas are more often seen in women already known with a brain tumor, while high-grade gliomas represent more frequently a new onset phenomenon. Based on these observations, guidelines are given on initiation of antitumor therapy during pregnancy, seizure management, counseling on therapeutic abortion, and on the timing and choice of obstetrical interventions.

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial.

BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. METHODS: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. FINDINGS: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. INTERPRETATION: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. FUNDING: EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.

Safety and pharmacokinetics of intravenous levetiracetam infusion as add-on in status epilepticus.

PURPOSE: To evaluate the feasibility and safety of intravenous (iv) levetiracetam (LEV) added to the standard therapeutic regimen in adults with status epilepticus (SE), and as secondary objective to assess a population pharmacokinetic (PK) model for ivLEV in patients with SE. METHODS: In 12 adults presenting with SE, 2,500 mg ivLEV was added as soon as possible to standardized protocol, consisting of iv clonazepam and/or rectal diazepam, as needed followed by phenytoin or valproic acid. ivLEV was administered over approximately 5 min, in general after administration of clonazepam, regardless the need for further treatment. During 24-h follow-up, patients were observed for any clinically relevant side-effects. Blood samples for PK analysis were available in 10 patients. A population PK model was developed by iterative two-stage Bayesian analysis and compared to PK data of healthy volunteers. RESULTS: Eleven patients with a median age of 60 years were included in the per protocol analysis. Five were diagnosed as generalized-convulsive SE, five as partial-convulsive SE, and one as a nonconvulsive SE. The median time from hospital admission to ivLEV was 36 min. No serious side effects could be related directly to the administration of ivLEV. During PK analysis, four patients showed a clear distribution phase, lacking in the others. The PK of the population was best described by a two-compartment population model. Mean (standard deviation, SD) population parameters included volume of distribution of central compartment: 0.45 (0.084) L/kg; total body clearance: 0.0476 (0.0147) L/h/kg; distribution rate constants, central to peripheral compartment (k(12)): 0.24 (0.12)/h, and peripheral to central (k(21)): 0.70 (0.22)/h. Mean maximal plasma concentration was 85 (19) mg/L. DISCUSSION: The addition of ivLEV to the standard regimen for controlling SE seems feasible and safe. PK data of ivLEV in patients with SE correspond to earlier values derived from healthy volunteers, confirming a two-compartment population model.

Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.

Epilepsy is common in patients with brain tumours and can substantially affect daily life, even if the tumour is under control. Several factors affect the mechanism of seizures in brain tumours, including tumour type, tumour location, and peritumoral and genetic changes. Prophylactic use of antiepileptic drugs is not recommended, and potential interactions between antiepileptic and chemotherapeutic agents persuades against the use of enzyme-inducing antiepileptic drugs. Multidrug-resistance proteins prevent the access of antiepileptic drugs into brain parenchyma, which partly explains why seizures are frequently refractory to treatment. Lamotrigine, valproic acid, and topiramate are first-line treatments of choice; if insufficient, add-on treatment with levetiracetam or gabapentin can be recommended. On the basis of clinical studies, we prefer to start treatment with valproic acid, adding levetiracetam if necessary. Risks of cognitive side-effects with antiepileptic drugs can add to previous damage by surgery or radiotherapy, and therefore appropriate choice and dose of antiepileptic drug is crucial.

CNS complications of breast cancer: current and emerging treatment options.

In general, the development of CNS metastases of breast cancer depends on several prognostic factors, including younger age and a negative hormone receptor status. Also, the presence of a breast cancer 1, early onset (BRCA1) germline mutation and expression of the human epidermal growth factor receptor 2 (Her2/neu) proto-oncogene seem to contribute to an increased rate of development of CNS metastases. The choice of appropriate therapy for brain metastases also depends on prognostic factors, including the age of the patient, the Karnofsky performance score, the number of brain metastases and the presence of systemic disease. Surgery followed by whole brain radiation therapy (WBRT) is generally restricted to ambulant patients with a single brain metastasis without active extracranial disease. In patients who have two to four metastases, stereotactic focal radiotherapy (i.e. radiosurgery) with or without WBRT is usually indicated. In the remainder of patients, WBRT alone provides adequate palliation. Although breast carcinoma is sensitive to chemotherapy, the role of chemotherapy in the treatment of brain metastases is still unclear. Objective responses after cyclophosphamide-based therapies were reported in studies performed in the 1980s. Subgroup analysis of data from a randomised study indicates that survival may improve if WBRT is combined with the radiosensitiser efaproxiral. Interestingly, the Her2/neu antibody trastuzumab, which does not cross the blood-brain barrier, produces systemic responses and enhanced survival, without a clear effect on brain metastases. Breast cancer constitutes the most common solid primary tumour leading to leptomeningeal disease. Clinical symptoms such as cranial nerve dysfunction or a cauda equina syndrome can be treated with local radiotherapy. A randomised study in patients with leptomeningeal disease secondary to breast cancer has revealed that intrathecal chemotherapy is associated with substantially more adverse effects than non-intrathecal treatment, without a clear benefit in terms of response or survival. Intramedullary metastasis is rare but often presents with a rapidly progressive myelopathy. Local radiotherapy may preserve neurological function. Epidural spinal cord metastasis occurs in approximately 4% of patients and can lead to paraplegia. A randomised study has shown that surgical intervention together with local radiotherapy is superior to local radiotherapy alone.

Central nervous system gliomas.

Evidence-based practical guidelines on diagnosis, prognosis, and treatment on the most frequent adult brain tumours are delineated. In Europe, 27,000 new cases of malignant glial tumours and 1000 new cases of malignant ependymal tumours are diagnosed every year. The most common glial tumours are glioblastoma multiforme and anaplastic glioma, comprising more than 50% and 10%, respectively, of the total gliomas. Prognosis of gliomas is generally poor. Environmental and genetic factors have been correlated with an increased risk of developing brain tumours. Surgical resection represents the first treatment option for all histotypes. Role and timing of radiotherapy and chemotherapy as well as treatment for recurrent/progressive disease should be based on age, performance status, histopathological diagnosis, molecular markers, and previous therapy. Impaired neurocognitive and neuropsychological function is common in long-term survivors, regardless of the histology and grade of the tumour and should be taken into account in treatment planning.

Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials.

Patients with low-grade glioma frequently have brain tumor-related epilepsy, which is more common than in patients with high-grade glioma. Treatment for tumor-associated epilepsy usually comprises a combination of surgery, anti-epileptic drugs (AEDs), chemotherapy, and radiotherapy. Response to tumor-directed treatment is measured primarily by overall survival and progression-free survival. However, seizure frequency has been observed to respond to tumor-directed treatment with chemotherapy or radiotherapy. A review of the current literature regarding seizure assessment for low-grade glioma patients reveals a heterogeneous manner in which seizure response has been reported. There is a need for a systematic approach to seizure assessment and its influence on health-related quality-of-life outcomes in patients enrolled in low-grade glioma therapeutic trials. In view of the need to have an adjunctive metric of tumor response in these patients, a method of seizure assessment as a metric in brain tumor treatment trials is proposed.

Seizures and gliomas--towards a single therapeutic approach.

Epilepsy often develops in patients with glioma, and the two conditions share common pathogenic mechanisms. Altered expression of glutamate transporters, including the cystine-glutamate transporter (xCT) system, increases concentrations of extracellular glutamate, which contribute to epileptic discharge, tumour proliferation and peripheral excitotoxicity. Furthermore, mutation of the isocitrate dehydrogenase 1 gene in low-grade gliomas causes production of D-2-hydroxyglutarate, a steric analogue of glutamate. Dysregulation of intracellular chloride promotes glioma cell mitosis and migration, and γ-aminobutyric acid (GABA) signalling suppresses proliferation. In neurons, however, chloride accumulation leads to aberrant depolarization on GABA receptor activation, thereby promoting epileptic activity. The molecular target of rapamycin (mTOR) pathway and epigenetic abnormalities are also involved in the development of tumours and seizures. Antitumour therapy can contribute to seizure control, and antiepileptic drugs might have beneficial effects on tumours. Symptomatic treatment with antiepileptic drugs carries risks of adverse effects and drug interactions. In this Review, we discuss the potential for single therapeutic agents, such as the xCT blocker sulfasalazine, the chloride regulator bumetanide, and the histone deacetylase inhibitor valproic acid, to manage both gliomas and associated epilepsy. We also provide guidance on the evidence-based use of antiepileptic drugs in brain tumours. The development of solo therapies to treat both aspects of gliomas promises to yield more-effective treatment with fewer risks of toxicity and drug interactions.

Seizures and cancer: drug interactions of anticonvulsants with chemotherapeutic agents, tyrosine kinase inhibitors and glucocorticoids.

Patients with cancer commonly experience seizures. Combined therapy with anticonvulsant drugs (AEDs) and chemotherapeutic drugs or tyrosine kinase inhibitors carries inherent risks on drug-drug interactions (DDIs). In this review, pharmacokinetic studies of AEDs with chemotherapeutic drugs, tyrosine kinase inhibitors, and glucocorticoids are discussed, including data on maximum tolerated dose, drug clearance, elimination half-life, and organ exposure. Enzyme-inducing AEDs (EIAEDs) cause about a 2-fold to 3-fold faster clearance of concurrent chemotherapeutic drugs metabolized along the same pathway, including cyclophosphamide, irinotecan, paclitaxel, and teniposide, and up to 4-fold faster clearance with the tyrosine kinase inhibitors crizotinib, dasatinib, imatinib, and lapatinib. The use of tyrosine kinase inhibitors, particularly imatinib and crizotinib, may lead to enzyme inhibition of concurrent therapy. Many of the newer generation AEDs do not induce or inhibit drug metabolism, but they can alter enzyme activity by other drugs including AEDs, chemotherapeutics and tyrosine kinase inhibitors. Glucocorticoids can both induce and undergo metabolic change. Quantitative data on changes in drug metabolism help to apply the appropriate dose regimens. Because the large individual variability in metabolic activity increases the risks for undertreatment and/or toxicity, we advocate routine plasma drug monitoring. There are insufficient data available on the effects of tyrosine kinase inhibitors on AED metabolism.

Epilepsy and brain tumors.

Seizures are common in patients with brain tumors, and epilepsy can significantly impact patient quality of life. Therefore, a thorough understanding of rates and predictors of seizures, and the likelihood of seizure freedom after resection, is critical in the treatment of brain tumors. Among all tumor types, seizures are most common with glioneuronal tumors (70-80%), particularly in patients with frontotemporal or insular lesions. Seizures are also common in individuals with glioma, with the highest rates of epilepsy (60-75%) observed in patients with low-grade gliomas located in superficial cortical or insular regions. Approximately 20-50% of patients with meningioma and 20-35% of those with brain metastases also suffer from seizures. After tumor resection, approximately 60-90% are rendered seizure-free, with most favorable seizure outcomes seen in individuals with glioneuronal tumors. Gross total resection, earlier surgical therapy, and a lack of generalized seizures are common predictors of a favorable seizure outcome. With regard to anticonvulsant medication selection, evidence-based guidelines for the treatment of focal epilepsy should be followed, and individual patient factors should also be considered, including patient age, sex, organ dysfunction, comorbidity, or cotherapy. As concomitant chemotherapy commonly forms an essential part of glioma treatment, enzyme-inducing anticonvulsants should be avoided when possible. Seizure freedom is the ultimate goal in the treatment of brain tumor patients with epilepsy, given the adverse effects of seizures on quality of life.

Therapeutic management of brain metastasis.

This review focuses on the management of brain metastases. The four main modes of therapy are discussed: whole brain radiation therapy (WBRT), surgery, radiosurgery, and chemotherapy. Young patients with limited extracranial disease may benefit from surgical resection of a single brain metastasis, and from radiosurgery (or stereotactic radiotherapy) if two to four brain metastases are present. Whether WBRT after surgery or radiosurgery is beneficial is uncertain. Therefore, two approaches can be justified in patients with a good prognosis: WBRT after surgery or radiosurgery, or alternatively, observation with MRI follow-up after surgery or radiosurgery. A hyperfractionated radiation scheme is then to be preferred to limit late toxicity of WBRT. Patients with extensive extracranial tumour activity or impaired quality of life may benefit from radiosurgery (one to four brain metastases), or from shorter WBRT schedules. We propose a decision tree on the various ways to treat brain metastasis.

Seizures in oligodendroglial tumors.

Epilepsy develops in more than 70-90% of oligodendroglial tumors and represents a favorable indicator for long-term survival if present as the first clinical sign. Presence of IDH1 mutation is frequently associated with seizures in oligodendrogliomas, next to alterations of glutamate and GABA metabolism in the origin of glioma-associated epilepsy. Treatment by surgery or radiotherapy results in seizure freedom in about two-thirds of patients, and chemotherapy to a seizure reduction in about 50%. Symptomatic anticonvulsive therapy with levetiracetam and valproic acid as monotherapy are both evidence-based drugs for the partial epilepsies, and their effective use in brain tumors is supported by a large amount of additional data. Pharmacoresistance against anticonvulsants is more prevalent among oligodendrogliomas, occurring in about 40% despite polytherapy with two anticonvulsants or more. Toxic signs of anticonvulsants in brain tumors involve cognition, bone marrow and skin. Previous neurosurgery, radiation therapy or chemotherapy add to the risks of cognitive dysfunction.

Interactions between antiepileptic and chemotherapeutic drugs.

Cancer and epilepsy commonly co-occur, and concomitant administration of antiepileptic (AEDS) and chemotherapeutic drugs (CTDs) is necessary in many cases. Many drugs are metabolised by the hepatic cytochrome P450 (CYP) isoenzyme system, and coadministration of AEDs and CTDs can lead to clinically relevant interactions by induction or inhibition of enzymes in shared metabolic pathways. These interactions can cause insufficient tumour and seizure control or lead to unforeseen toxicity. Enzyme-inducing AEDs reduce the effects of taxanes, vinca alkaloids, methotrexate, teniposide, and camptothecin analogues. Inhibition of the metabolism of nitrosoureas or etoposide by valproic acid can lead to CTD toxicity. Poor seizure control may result from the combinations of phenytoin with cisplatin or corticosteroids, and valproic acid with methotrexate. Increased toxicity of AEDs can occur when phenytoin is combined with 5-fluorouracil. Use of enzyme-inducing AEDs should be avoided in patients with cancer, particularly in association with chemotherapy. Generally, valproic acid-although not free from interactions-would be the agent of first choice. Some of the newer AEDs not metabolised by the P450 system may prove to be good alternatives.

Treating seizures in patients with brain tumors: Drug interactions between antiepileptic and chemotherapeutic agents.

Seizures are a common complication in patients with primary brain tumors or brain metastases that require treatment with antiepileptic drugs (AEDs). However, because many AEDs and chemotherapeutics share common metabolic pathways via the hepatic cytochrome P450 (CYP) isoenzymes, there is potential for drug interactions. Phenytoin, carbamazepine, and phenobarbital are potent enzyme-inducing AEDs (EIAEDs) that can cause a decrease in the serum concentration of chemotherapeutics, potentially compromising antitumor activity. Likewise, chemotherapeutics can alter the pharmacokinetics of EIAEDs, resulting in decreased seizure control. Other agents, such as valproic acid, are enzyme-inhibiting AEDs that can impede the metabolism of other drugs, potentially increasing the serum concentration of chemotherapeutics. Therefore, patients receiving valproic acid with concomitant chemotherapy should be monitored closely. A new generation of AEDs that are not metabolized by CYP isoenzymes is currently being developed. Of these, gabapentin and levetiracetam show the most promise in treating epileptic seizures in patients with brain tumors. Interactions between these newer AEDs and chemotherapeutic agents have not been reported. In summary, the potential interactions between AEDs and chemotherapy should be anticipated and appropriate proactive adjustments implemented. Future studies will define the role of newer AEDs in the treatment of patients with primary brain tumors.

Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme.

BACKGROUND: To examine the efficacy of valproic acid (VPA) given either with or without levetiracetam (LEV) on seizure control and on survival in patients with glioblastoma multiforme (GBM) treated with chemoradiation. METHODS: A retrospective analysis was performed on 291 patients with GBM. The efficacies of VPA and LEV alone and as polytherapy were analyzed in 181 (62%) patients with seizures with a minimum follow-up of 6 months. Cox-regression survival analysis was performed on 165 patients receiving chemoradiation with temozolomide of whom 108 receiving this in combination with VPA for at least 3 months. RESULTS: Monotherapy with either VPA or LEV was instituted in 137/143 (95.8%) and in 59/86 (68.6%) on VPA/LEV polytherapy as the next regimen. Initial freedom from seizure was achieved in 41/100 (41%) on VPA, in 16/37 (43.3%) on LEV, and in 89/116 (76.7%) on subsequent VPA/LEV polytherapy. At the end of follow-up, seizure freedom was achieved in 77.8% (28/36) on VPA alone, in 25/36 (69.5%) on LEV alone, and in 38/63 (60.3%) on VPA/LEV polytherapy with ongoing seizures on monotherapy. Patients using VPA in combination with temozolomide showed a longer median survival of 69 weeks (95% confidence interval [CI]: 61.7-67.3) compared with 61 weeks (95% CI: 52.5-69.5) in the group without VPA (hazard ratio, 0.63; 95% CI: 0.43-0.92; P = .016), adjusting for age, extent of resection, and O(6)-DNA methylguanine-methyltransferase promoter methylation status. CONCLUSIONS: Polytherapy with VPA and LEV more strongly contributes to seizure control than does either as monotherapy. Use of VPA together with chemoradiation with temozolomide results in a 2-months' longer survival of patients with GBM.