lacosamide and Brain-Neoplasms

A concise review of recent findings in brain tumor-related epilepsy (BTRE), with focus on the effect of antitumor treatment on seizure control and the management of antiepileptic drugs (AEDs).. Isocitrate dehydrogenase mutation and its active metabolite d -2-hydroxyglutarate seem important contributing factors to epileptogenesis in BTRE. A beneficial effect of antitumor treatment (i.e. surgery, radiotherapy, and chemotherapy) on seizure control has mainly been demonstrated in low-grade glioma. AED prophylaxis in seizure-naïve BTRE patients is not recommended, but AED treatment should be initiated after a first seizure has occurred. Comparative efficacy randomized controlled trials (RCTs) are currently lacking, but second-generation AED levetiracetam seems the preferred choice in BTRE. Levetiracetam lacks significant drug-drug interactions, has shown favorable efficacy compared to valproic acid in BTRE, generally causes no hematological or neurocognitive functioning adverse effects, but caution should be exercised with regard to psychiatric adverse effects. Potential add-on AEDs in case of uncontrolled seizures include lacosamide, perampanel, and valproic acid. Ultimately, in the end-of-life phase when oral intake of medication is hampered, benzodiazepines via nonoral administration routes are potential alternatives.. Management of seizures in BTRE is complex and with currently available evidence levetiracetam seems the preferred choice. Comparative efficacy RCTs in BTRE are warranted.

Topics: Anticonvulsants; Benzodiazepines; Brain Neoplasms; Epilepsy; Humans; Isocitrate Dehydrogenase; Lacosamide; Levetiracetam; Seizures; Valproic Acid

To evaluate the effectiveness and tolerability of lacosamide added to one or two antiepileptic drugs (AEDs) in the treatment of patients with brain tumor-related epilepsy (BTRE), and to evaluate patients' global impression of change and quality of life (QoL).. This was a prospective, multicenter, single-arm, noninterventional study with a 6-month observation period (EP0045; NCT02276053). Eligible patients (≥16 years old) had active BTRE secondary to low-grade glioma (World Health Organization grade 1 and 2) and were receiving treatment with one or two AEDs at baseline. Lacosamide was initiated by the treating physician in the course of routine clinical practice. Primary outcomes were 50% responders (≥50% reduction in focal seizure frequency from baseline) and Patient's Global Impression of Change (PGIC) at month 6. Secondary outcomes included seizure-free status and Clinical Global Impression of Change (CGIC) at month 6, change in QoL (5-Level EuroQol-5 Dimension Quality of Life Assessment) and symptom outcomes (MD Anderson Symptom Inventory-Brain Tumor) from baseline to month 6, and Kaplan-Meier estimated 6-month retention on lacosamide. Safety variables included adverse drug reactions (ADRs).. Patients were recruited from 24 sites in Europe. Ninety-three patients received lacosamide (mean [standard deviation] age = 44.5 [14.7] years; 50 [53.8%] male; median baseline focal seizure frequency = five seizures/28 days [range = 1-280]), of whom 79 (84.9%) completed the study. At 6 months, 66 of 86 (76.7%) patients were 50% responders and 30 of 86 (34.9%) were seizure-free. Improvements on PGIC were reported by 49 of 76 (64.5%) patients. Based on CGIC, 52 of 81 (64.2%) patients improved. QoL and symptoms outcome measures remained stable. Kaplan-Meier estimated 6-month retention rate was 86.0% (N = 93). Fifteen (16.1%) patients reported ADRs; four (4.3%) had ADRs leading to discontinuation (N = 93).. Results of this prospective, noninterventional study suggest that add-on lacosamide is effective and generally well tolerated in patients with BTRE.

Topics: Adult; Anticonvulsants; Brain Neoplasms; Chemotherapy, Adjuvant; Drug Therapy, Combination; Epilepsy; Female; Humans; Lacosamide; Male; Middle Aged; Prospective Studies; Quality of Life; Treatment Outcome

Lacosamide (LCM) is an antiepileptic drug (AED) that has demonstrated a good efficacy in controlling seizures as an add-on in adult epilepsy. To date, there have been no studies on LCM in patients with brain tumor-related epilepsy (BTRE). To evaluate efficacy and tolerability of LCM as an add-on in BTRE, we followed 14 patients suffering from BTRE who had already been treated with other AEDs and who had not experienced adequate seizure control. Eleven patients underwent chemotherapy while being treated with LCM. Mean duration of follow up was 5.4 months (min < 1 max 10 months). Mean seizure number in the last month prior to the introduction of LCM had been 15.4. At last follow-up, the mean seizure number was reduced to 1.9/month. Lacosamide mean dosage was of 332.1 mg/day (min 100 max 400 mg/day). Responder rate was 78.6%. One patient discontinued LCM because of side-effects. There were no other reported side-effects. Preliminary data on the use of LCM in add-on in patients with BTRE indicate that this drug may represent a valid alternative as an add-on in this particular patient population. However, larger samples are necessary in order to draw definitive conclusions.

Topics: Acetamides; Adult; Anticonvulsants; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Epilepsy; Female; Humans; Lacosamide; Male; Middle Aged; Young Adult

Lacosamide (LCM) is a third-generation anti-seizure medication (ASM) approved for focal onset epilepsy in patients aged ≥ 4.378 Previous studies have reported an efficacy of LCM as add-on treatment in brain tumor-related epilepsy (BTRE). To date, there are no studies in the literature focusing on lacosamide used in monotherapy to treat BTRE. In our retrospective study we investigated efficacy and tolerability of LCM in monotherapy in a multicenter national cohort of primary brain tumor patients.. We collected from 12 Italian Centers 132 patients with primary brain tumors who were treated with LCM in monotherapy. For each patient we evaluated seizure freedom at 3 and 6 months (primary endpoints), side effects and drop-out rate (secondary endpoints).. Overall, LCM led to seizure freedom in 64.4% of patients at 3 months and 55% at 6 months. Patients who used two or more ASMs before LCM had a worse seizure control than patients in monotherapy with LCM as first choice. In 14 patients, we observed seizure control despite tumor progression on magnetic resonance (MRI). Multivariate analysis showed that gross-total resection at diagnosis was significantly associated with higher seizure freedom rate at 6 months. Side effects were mainly mild (grade 1-2 according to CTCAE classification) and drop-out rate was low (1.5%). Main side effects were dizziness and somnolence.. This is the first study showing a good efficacy and tolerability of LCM when used in monotherapy in BTRE. Further prospective studies are needed to confirm these preliminary data, investigating also quality of life and neurocognitive functions.

Topics: Acetamides; Anticonvulsants; Brain Neoplasms; Drug-Related Side Effects and Adverse Reactions; Epilepsies, Partial; Epilepsy; Humans; Lacosamide; Quality of Life; Retrospective Studies; Seizures; Treatment Outcome

Glioblastoma (GBM) is an aggressive primary brain tumor. The rapid growth and the privileged provenance of the tumor within the brain contribute to its aggressivity and poor therapeutic targeting. A poor prognostic factor in glioblastoma is the deletion or mutation of the Nf1 gene. This gene codes for the protein neurofibromin, a tumor suppressor gene that is known to interact with the collapsin response mediator protein 2 (CRMP2). CRMP2 expression and elevated expression of nuclear phosphorylated CRMP2 have recently been implicated in cancer progression. The CRMP2-neurofibromin interaction protects CRMP2 from its phosphorylation by cyclin-dependent kinase 5 (Cdk5), an event linked to cancer progression. In three human glioblastoma cell lines (GL15, A172, and U87), we observed an inverse correlation between neurofibromin expression and CRMP2 phosphorylation levels. Glioblastoma cell proliferation was dependent on CRMP2 expression and phosphorylation by Cdk5 and glycogen synthase kinase 3 beta (GSK3β). The CRMP2 phosphorylation inhibitor (S)-lacosamide reduces, in a concentration-dependent manner, glioblastoma cell proliferation and induced apoptosis in all three GBM cell lines tested. Since (S)-lacosamide is bioavailable in the brain, we tested its utility in an in vivo orthotopic model of GBM using GL261-LucNeo glioma cells. (S)-lacosamide decreased tumor size, as measured via in vivo bioluminescence imaging, by ~54% compared to vehicle control. Our results introduce CRMP2 expression and phosphorylation as a novel player in GBM proliferation and survival, which is enhanced by loss of Nf1.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Glioblastoma; Humans; Intercellular Signaling Peptides and Proteins; Lacosamide; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurofibromin 1; Phosphorylation

Lacosamide is an antiepileptic drug (AED), which has proven to be effective to control seizures, including acute conditions such as status epilepticus. The aim of this study is to describe the clinical experience with lacosamide in neuro-oncological patients.. Multicenter retrospective study in patients with cancer-related seizures, who received lacosamide as an add-on therapy.. Forty-eight patients with benign and malignant tumors, including primary brain tumors, lymphomas, systemic cancer with central nervous system involvement, or paraneoplastic encephalitis, were included. Lacosamide was effective in the control of chronic seizures in patients with either benign or malignant tumors. The success rate was greater in malignant tumors, and drug-resistant epilepsies were more likely associated with benign tumors. Adverse events occurred in nearly 70% of patients, particularly in acute conditions and associated with the concomitant use of radio-/chemotherapy. Lacosamide-related adverse events were more likely somnolence and dizziness, which usually resolved after dose adjustment. After starting lacosamide, nearly half of the patients discontinued one of the baseline AEDs and decreased or discontinued dexamethasone. Fifteen patients with status epilepticus were treated with intravenous lacosamide, and 73% of them had their condition resolved without serious drug-related adverse events.. Lacosamide is an AED to consider in cases of cancer-related seizures. Lacosamide pharmacodynamics and pharmacokinetics allow the achievement of responder rates over 50% with no serious adverse effects, amelioration of side effects from other AEDs or radio-/chemotherapy, and no significant drug interactions. Furthermore, the intravenous formulation shows clear benefits in acute conditions such as status epilepticus.

Topics: Acetamides; Adult; Aged; Aged, 80 and over; Anticonvulsants; Brain Neoplasms; Female; Humans; Lacosamide; Male; Middle Aged; Retrospective Studies; Seizures; Treatment Outcome; Young Adult

To report the efficacy and tolerability of lacosamide as an add-on treatment in patients with gliomas and uncontrolled seizures despite conventional antiepileptic drugs (AEDs). We conducted an observational study on 71 patients to describe patterns of response to lacosamide and the association between clinico-pathological factors and seizure control. We observed at 3, 6 and 9 months a seizure reduction ≥ 50% in 74.6, 76 and 86.2% of patients and a seizure freedom in 42.2, 43 and 50%, respectively. The median number of seizures in the 3 months before treatment was 13, and decreased to 3 between baseline and 6 months, and to 0.5 between 6 and 9 months. The best seizure response was observed at 3 months (62%). Sixty per cent of patients displayed the maximum seizure control with doses of lacosamide of 100-250 mg/day, while 21% needed doses up to 400 mg/day. Seizure reduction ≥ 50% and seizure freedom were higher in patients who received lacosamide as first add-on compared to those who received a later adjunctive therapy. A reduction ≥ 50% of seizures was observed in a proportion of patients with progressive disease on MRI. Age > 45 years (OR 0.11, 95% CI 0.02-0.63, p = 0.013) was a significant predictor of seizure freedom at 9 months on multivariate analysis. The study suggests that lacosamide, when added to any baseline AEDs, is effective in obtaining a high seizure reduction and seizure freedom regardless of the tumor activity and response to antineoplastic therapies.

Topics: Adult; Anticonvulsants; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Glioma; Humans; Lacosamide; Male; Middle Aged; Seizures; Treatment Outcome

Therapeutic doses of antiepileptic drugs (AEDs) may alter EEG background activity, which is considered an index of the functional state of the brain. Quantitative analysis (qEEG) of EEG background activity is a valid instrument to assess the effects of many centrally active drugs on the central nervous system, including AEDs. Lacosamide (LCM) is a new AED that could be a valid therapeutic choice in patients with brain tumor-related epilepsy (BTRE).. We used qEEG to analyze the possible effect of LCM as an add-on, on background EEG activity after 4 months in patients with BTRE.. We consecutively recruited sixteen patients with BTRE: Five dropped out for disease progression, five for scarce compliance, and six completed the study. For these reasons qEEG was performed at first visit and after 4 months only in six patients. For all frequency bands, LCM revealed no changes of mean relative power during rest with eyes closed, hyperpnoea (HP), and mental arithmetic task (MA); significant increment was found only in the theta mean relative power during opening and closing eyes (BR). After four months of therapy with LCM, one patient was seizure free, four had a seizure reduction ≥50%, and one showed a worsening in seizure frequency <50%.. Despite the limitation of a small series, these findings suggest that LCM seems to have only a mild interference on EEG background activity and confirm that LCM has a good efficacy on seizure control in patients with BTRE. This is the first study that evaluates the effect of LCM on background EEG activity, using qEEG in BTRE patients. Future research in this area could include prospective studies with qEEG for a longer follow-up period to assess the impact of AEDs on brain functions in this particular fragile patient population.

Topics: Adult; Anticonvulsants; Brain Neoplasms; Disease Progression; Electroencephalography; Epilepsy; Female; Glioma; Humans; Lacosamide; Male; Middle Aged; Psychological Tests; Research Design; Rest; Seizures

Lacosamide (LCM) due to no known drug interaction and the absence of metabolic enzyme induction is a good candidate for an add-on medication, especially in combination with lamotrigine, levetiracetam (LEV), oxcarbazepine, topiramate, and valproic acid (VPA). Here we report for the first time, to our knowledge, that LCM can lower VPA and LEV serum levels. At present, there are no known explicable mechanisms of action of LCM, which lowers VPA and LEV. Here observed drug interaction of LCM is of clinical significance, which might be useful for other colleagues in the field.

Topics: Acetamides; Adolescent; Anticonvulsants; Brain Neoplasms; Drug Interactions; Epilepsies, Partial; Humans; Lacosamide; Levetiracetam; Neoplasms, Neuroepithelial; Piracetam; Seizures; Valproic Acid

Brain tumor-related epilepsy (BTRE) is often drug resistant and patients can be forced to take polytherapy that can adversely affect their quality of life (QoL). Lacosamide (LCM) is a new antiepileptic drug (AED) used as adjunctive therapy in patients with partial seizures with or without secondary generalization, with a favorable pharmacokinetic profile that seems to be effective and well tolerated. Therefore it represents a possible therapeutic choice for patients with BTRE. We propose a prospective study with a historical control group to evaluate the effect of LCM as add-on therapy on seizure control and quality of life in patients with BTRE. This study has been designed to test the superiority of Lacosamide over Levetiracetam as an add-on. We compared a prospective cohort of 25 patients treated with Lacosamide with a historical control group (n=19) treated with Levetiracetam as an add-on.. We recruited 25 adult patients (M 18, F 7; mean age 41.9) affected by BTRE with uncontrolled partial-onset seizures treated with AED polytherapy. We added LCM as an add-on. Patients were evaluated at baseline, after 3months and at 6months. This population has been compared with a historical control group of 19 BTRE adult patients (M 13, F 6; median age 48.0, range: 28-70) with uncontrolled partial-onset seizures treated with LEV as add-on. The patients underwent QoL, mood and adverse events tests (Adverse Event Profile-AEP) and evaluation of seizure frequency.. Twelve patients had high grade gliomas, and thirteen had low grade gliomas. During follow-up, thirteen patients underwent chemotherapy, three radiotherapy and five patients had disease progression. Nine patients had simple partial seizures, eight had complex partial seizures, and eight had secondary generalized seizures. Fifteen patients were in monotherapy and ten in polytherapy with AEDs. LCM was added up to reach the maximum dosage of 400mg/die (mean final dose 300mg/die). Four patients dropped out due to poor compliance and 1 for inefficacy. In the historical control group treated with LEV (mean final dose 2000mg/die) 12 patients had high-grade gliomas, and 7 had low grade gliomas. Thirteen patients were in monotherapy and 6 in polytherapy with AEDs. In the 22 patients evaluable of 25 patients treated with LCM, we observed at final follow-up 7 patients seizure free, 12 with a significant reduction of seizures≥50%, 2 stable and 1 patient with number of seizures increased. Mean seizure frequency at baseline compared with baseline period: the mean number of seizures significantly decreased from baseline (9.4) to final follow-up (1.2) (P=0.005). The Responder Rate was 86.4%. Comparing responder rate of 22 evaluable patients with LCM with responder rate of 19 patients with LEV we didn't observe significant differences (p=0.31). In our patients treated with LCM we didn't observe significant difference at 3 and 6months in QoL tests results; we observe a significant reduction in the mean score of Karnofsky Performance Status (KPS) and Barthel Index (BI) between baseline and 6months of follow-up (KPS p=0.003; BI p=0.007). No clinical side effects were observed.. Comparing the LCM with the historical group treated with LEV in add-on, we observed that LCM seems to have a higher clinical efficacy than LEV. In our patients, we did not observe any significant changes in QoL tests, indicating stability in all quality of life domains explored, despite the objective worsening in their functional status. Although this is a small series with a relatively short follow-up, our data indicates that LCM in add-on in patients with BTRE appears to be as effective as LEV in add-on, without impact on mood and quality of life.

Topics: Acetamides; Adult; Affect; Aged; Anticonvulsants; Brain Neoplasms; Drug Therapy, Combination; Epilepsies, Partial; Epilepsy; Female; Historically Controlled Study; Humans; Lacosamide; Levetiracetam; Male; Middle Aged; Outcome Assessment, Health Care; Piracetam; Prospective Studies; Quality of Life

Topics: Acetamides; Adult; Anticonvulsants; Astrocytoma; Brain Neoplasms; Fatal Outcome; Humans; Injections, Subcutaneous; Lacosamide; Male; Palliative Care; Seizures

The choice of antiepileptic drug (AED) therapy in patients with brain tumor-related epilepsy (BTRE) is complicated, and there are a lack of robust clinical trial data to date.. The NEOPLASM (Neuroncologic Patients treated with LAcoSaMide) study was a 6-month, multicenter, retrospective, observational study in patients with BTRE treated with lacosamide. Patients were started on lacosamide because of a lack of efficacy or adverse events (AEs) with prior AEDs or suitability versus other AEDs, according to clinical practice. The primary efficacy variable was the seizure-free rate at 6months. Safety variables included the proportion of patients with an AE and the proportion with an AE that led to discontinuation.. Overall, 105 patients from 14 hospital centers were included in the analysis. Treatment with lacosamide for 6months resulted in a 30.8% seizure-free rate, and 66.3% of patients had a ≥50% seizure reduction (responders). In the subset of patients included because of a lack of efficacy with prior AEDs, seizure-free rates were 28.0%, and 66.7% of patients were responders. No statistically significant differences in efficacy were observed according to the mechanism of action or enzyme-inducing properties of concomitant AEDs. Adverse events were reported by 41.9% of patients at 6months, and 4.7% of them led to discontinuation. The most common AEs were somnolence/fatigue and dizziness. Notably, 57.1% of the patients who were switched to lacosamide because of AEs with their previous therapy did not report any AE at 6-month follow-up.. In this open-label, observational study, lacosamide appeared to be effective and well tolerated in a large population of patients with BTRE. Lacosamide may therefore be a promising option for the treatment of patients with BTRE.

Topics: Acetamides; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Brain Neoplasms; Epilepsy; Female; Follow-Up Studies; Humans; Lacosamide; Male; Middle Aged; Retrospective Studies; Seizures; Treatment Outcome; Young Adult

The site of action for antiepileptic drugs (AEDs) is within the brain; however, cerebrospinal fluid (CSF) concentration is highly variable. Lacosamide (LCM) is approved by the U.S. Food and Drug Administration (FDA) for treatment of partial-onset seizures in adults, and has linear pharmacokinetics in serum. Penetration across the blood-brain barrier (BBB) is unknown. This study aims to provide additional insights into the pharmacokinetics of LCM.. Thirty adults undergoing craniotomy for treatment of intractable epilepsy or brain tumor were recruited and were either taking LCM long term (group 1, n = 15), or were LCM naive, receiving LCM as prophylaxis for surgery (group 2, n = 15). All patients received one intravenous (IV) dose (15 min infusion) immediately prior to craniotomy. CSF and arterial blood were collected simultaneously following craniotomy. LCM concentrations were measured in serum and CSF.. LCM concentration differences between groups 1 and 2 for both CSF and serum were statistically significant (p ≤ 0.0005), but there was no statistically significant difference in CSF/serum ratios (group 1 = 0.726 ± 0.231; group 2 = 0.556 ±0.241; p = 0.0585). LCM concentration in serum correlated positively with CSF concentration in group 1 (Pearson r = 0.8527, p < 0.0001). The time interval between the end of dose delivery and sample collection correlated positively with the CSF/serum ratio for the drug-naive group (Pearson r = 0.6525; p = 0.0084). Treatment with other AEDs did not affect LCM distribution between serum and CSF.. Although chronic dosing resulted in higher LCM concentrations in serum and CSF compared to drug-naive patients, the CSF/serum ratio was not affected by LCM pretreatment. These data suggest that LCM serum concentration may reliably predict CSF concentration.

Topics: Acetamides; Adolescent; Adult; Aged; Anticonvulsants; Blood-Brain Barrier; Brain Neoplasms; Craniotomy; Drug Administration Schedule; Epilepsy; Female; Humans; Lacosamide; Male; Middle Aged; Young Adult

The object of this study was to determine the tolerability and activity of lacosamide in patients with brain tumors.. The authors reviewed the medical records at 5 US academic medical centers with tertiary brain tumor programs, seeking all patients in whom a primary brain tumor had been diagnosed and who were taking lacosamide.. The authors identified 70 patients with primary brain tumors and reviewed seizure frequency and toxicities. The majority of the patients had gliomas (96%). Fifty-five (78%) had partial seizures only, and 12 (17%) had generalized seizures. Most of the patients (74%) were started on lacosamide because of recurrent seizures. Forty-six patients (66%) reported a decrease in seizure frequency, and 21 patients (30%) reported stable seizures. Most of the patients (54 [77%]) placed on lacosamide did not report any toxicities.. This retrospective analysis demonstrated that lacosamide was both well tolerated and active as an add-on antiepileptic drug (AED) in patients with brain tumors. Lacosamide's novel mechanism of action will allow for concurrent use with other AEDs, as documented by its activity across many different types of AEDs used in this patient population. Larger prospective studies are warranted.

Topics: Acetamides; Adult; Anticonvulsants; Brain Neoplasms; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Glioblastoma; Humans; Lacosamide; Male; Middle Aged; Prevalence; Retrospective Studies; Secondary Prevention; Seizures; Treatment Outcome

Topics: Acetamides; Anticonvulsants; Brain Neoplasms; Female; Humans; Lacosamide; Male; Seizures