Efficacy and tolerability of lacosamide for secondary epileptic seizures in patients with brain tumor: A multicenter, observational retrospective study
Corrigendum in: /10.3892/ol.2017.6689
- Authors:
- Published online on: April 5, 2017 https://doi.org/10.3892/ol.2017.5988
- Pages: 4093-4100
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Copyright: © Sepúlveda‑Sánchez et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Epileptic seizures are a frequent and limiting complication in patients with brain cancer that can also occur in patients with systemic cancer (1–5). In total, ≤50% of patients with brain tumors are expected to have an epileptic seizure during the course of their disease (4). Seizure management is crucial in primary and metastatic brain tumors, but may be complicated (6). The main treatments available are antiepileptic drugs (AEDs). In patients with brain tumors who are experiencing seizures, the adverse events (AEs) and drug interactions associated with traditional AEDs are observed more frequently, compared with in the general population of patients with epilepsy (6,7). A number of the traditional AEDs interact with corticosteroids, a universal treatment for brain tumors, reducing their efficacy (8–10). Certain AEDs also interact with cytochrome P450, causing the accelerated metabolism of the majority of chemotherapeutic agents (11,12). Furthermore, the metabolism of AEDs can be altered by corticosteroids and chemotherapies, leading to under- and overdosing (13,14). Therefore, it is essential to identify an AED that has proven efficacy, low and/or manageable toxicity with low drug-drug interactions and is easy to titrate.
Lacosamide is a third-generation AED that selectively enhances the slow inactivation of voltage-gated sodium channels (15). The drug is approved in the USA and EU for use as an adjunctive therapy, and in the USA for use as monotherapy in the treatment of focal epilepsies. The efficacy and tolerability of lacosamide is well established (16–18). Lacosamide has a favorable pharmacokinetic profile with low protein binding and a low potential for drug-drug interactions (15), and is available as an intravenous formulation.
To date, few studies have investigated the use of lacosamide in patients with epileptic seizures due to brain tumors. However, there is data from routine clinical practice that suggests promising efficacy and tolerability in this patient population: A retrospective chart review of 70 patients with brain tumors in the USA found that lacosamide was well tolerated and demonstrated effectiveness when used as an add-on AED treatment (19). The aim of the present study was to investigate the efficacy and tolerability of lacosamide in controlling epileptic seizures in patients with brain tumors in Spain.
Materials and methods
Study design and patients
This observational retrospective study was conducted at six centers in Spain: Hospital Provincial de Castellón (Castellón), Hospital 12 de Octubre (Madrid), Hospital General de Castellón (Castellón), Hospital Universitario Rey Juan Carlos (Madrid), University Hospital La Fe (Valencia) and Hospital Universitario Fundación Alcorcón (Madrid). Data from patients ≥18 years of age who had received at least one dose of lacosamide for seizure management were collected. Criteria for study eligibility depended upon the attending neurologist's criteria, and included at least one convulsive seizure episode due to a brain tumor and subsequent placement on lacosamide as an anticonvulsant treatment. Resistance to previous AEDs was established following routine clinical practice procedures at each study center. Epilepsy was diagnosed based on the physician's clinical experience and symptoms indicative of epilepsy. All patients (or their guardian) provided written informed consent prior to inclusion in the present analysis. Patients were excluded if they were receiving any experimental drug other than lacosamide. The present study was conducted according to the principles of the Declaration of Helsinki and the study protocol was reviewed and approved by the Ethics Committee of Hospital Provincial de Castellón (Castellón, Spain).
Data collection
Data was collected by reviewing the medical records of patients and included patient demographics (age, gender, comorbidities, smoking status), tumor histology, functional status [as per the Eastern Cooperative Oncology Group criteria (20)], cancer treatment, seizure type, mean number of seizures and the number of previous and concomitant AEDs.
Treatment outcomes
The primary objective was to assess the effectiveness of lacosamide in patients with secondary epileptic seizures by comparing the number of seizures experienced by the patient prior to and subsequent to lacosamide treatment (at 3 and 6 months). An additional measure of efficacy was the need to progress to combination AED therapy [lacosamide + other AED(s)] to achieve seizure control. The secondary objective was to assess the tolerability of lacosamide (via reported AEs). The efficacy population included all patients who were still receiving lacosamide treatment at 3 months. All patients who received at least one dose of lacosamide during the study were included in the safety analysis. A subgroup analysis was performed to determine the efficacy and safety of lacosamide in patients who experienced a lack of efficacy from previous AEDs.
Statistical analysis
Statistical analyses for the present study were performed using the software package SAS version 9.3 (SAS Institute Inc., Cary, NC, USA). All variables were analyzed by summary statistical methods. For continuous variables, descriptive statistics including the arithmetic mean, standard deviation (SD), median, interquartile range and the minimum and maximum values were used. Continuous variable data were collected at the baseline, and at 3 and 6 months. For qualitative variables, absolute and relative frequency tables were generated. Continuous variables were assessed using the Student's t-test or the Wilcoxon signed-rank test when variables did not meet the normality criteria. For categorical variables, P-values were calculated using the χ2 test, or the Fisher's exact test when the criteria for the χ2 test were not fulfilled. P<0.05 was considered to indicate a statistically significant difference.
Considering the patient characteristics, it was assumed that, following 3 months of lacosamide treatment, 16% of patients would exhibit a ≥50% decrease in the number of seizures. Based on this, a total of 47 evaluable patients were required to achieve an accuracy of 10%, assuming a confidence level of 95%. Another hypothesis examined in the present study was that lacosamide would produce a decrease of ~30% in the number of seizures with an estimated standard deviation of 60%. A sample of 46 patients was required to detect these differences as statistically significant using a Wilcoxon signed-rank test paired with a power of 90%. However, only 39 patients were found eligible for the present study.
Results
Patient characteristics
Between July 2013 and November 2013, data from 39 patients with a brain tumor-associated epileptic seizure who had received lacosamide as an anticonvulsant were collected and included in the present analysis. The patients were distributed across the six medical centers as follows: Hospital Provincial de Castellón, n=8; Hospital 12 de Octubre, n=11; Hospital General de Castellón, n=2; Hospital Universitario Rey Juan Carlos, n=6; Hospital Universitari i Politècnic La Fe, n=4; Hospital Universitario Fundación Alcorcón, n=8. Patients had a mean age of 54.1±13.8 years and 66.7% were male (Table I). The majority of patients (n=30; 76.9%) presented with a single brain lesion, and multiple brain lesions were reported in 9 (23.1%) patients. Prior to the initiation of lacosamide treatment, patients had experienced a mean of 21.8 seizures (range, 0–200; SD 43.4) in the previous 3 months. The most common type of seizure experienced prior to treatment was a simple partial seizure. Of the 39 patients included in the study, 3- and 6-months of data were available for 33 (84.6%) and 26 (66.7%) patients, respectively (Table II). The reasons for the unavailable 6-month data in 13 patients were: Cancer-associated mortality (n=7; 53.8%); change of address (n=2); data not recorded (n=2); withdrawal from the study prior to completion (n=1); and lacosamide treatment withdrawn due to a lack of effectiveness (n=1). A total of 30 patients were eligible for the subgroup analysis (Table I), from which 19 patients (63.3%) completed the study. The reasons for the unavailability of 6-month data in the subgroup were: Cancer-associated mortality (n=7), withdrawal from the study prior to completion (n=3), and lost to follow-up (n=1).
 | Table II.Histological diagnosis, oncology treatment and the number of seizures reported in the study patients prior to and subsequent to lacosamide treatment. |
Lacosamide treatment
The main reason for the initiation of lacosamide treatment was the inefficacy of other prior AEDs (76.9% of patients), followed by a lack of tolerance to previous AEDs (12.8%). At the initiation of treatment, patients received a mean dose of 138.5±68.3 mg/day of lacosamide. The majority (66.7%) of patients initiated treatment at a dose of 100 mg/day. The most commonly used AEDs at the initiation of lacosamide treatment were levetiracetam (84.6% of patients) and valproic acid (20.5%).
While receiving lacosamide, nine patients modified their lacosamide treatment; seven due to a lack of efficacy and two due to AEs. Of these, lacosamide was discontinued in one patient due to dermal toxicity, which improved subsequent to the discontinuation of lacosamide. The remaining lacosamide modifications were an increase in dose. Two patients reported a lack of efficacy with lacosamide and one other patient reported unacceptable AEs; however, the dose of lacosamide those patients received remained unchanged.
In the subgroup analysis, the mean dose of lacosamide was 123.3±55.29 mg/day, with the majority of patients (70%) receiving an initial dose of 100 mg/day. The most frequently used AEDs with lacosamide in the subgroup were levetiracetam (93.33%) and valproic acid (23.33%).
Concomitant medications
Table III depicts the concomitant treatments received by the patients during the study period. The most common concomitant AED administered during the present study with lacosamide treatment was levetiracetam (94.3% of patients). A total of 8 patients modified their concomitant AEDs over the study period. A total of 4 patients reduced their levetiracetam dose; 1 patient discontinued carbamazepine and reduced their dose of valproic acid; 1 patient initiated treatment with eslicarbazepine acetate and carbamazepine (which was later discontinued); 1 patient initiated treatment with valproic acid; 1 patient reduced the dose of valproic acid.
A total of 18 patients also received concomitant treatment with a corticosteroid during the study period (Table III). Patients who received dexamethasone modified their concomitant treatment: 5 patients reduced their dose and 1 patient increased the dose. No additional modifications to the concomitant corticosteroid treatment were made during the study period. No drug-interaction between lacosamide and radiotherapy, or lacosamide and chemotherapy was observed.
In the subgroup analysis, all patients received lacosamide in combination with another drug. The numbers of concomitant treatments used were 1, 2, 4 and 6 in 60, 33.33, 3.33 and 3.33% of patients, respectively. A total of 29 patients (96.7%) received levetiracetam and lacosamide. Table III details the anticancer therapy received by each of the patients included in the subgroup analysis. No interaction between lacosamide and chemotherapy or radiotherapy was reported.
Treatment effectiveness
The number of seizures from the initiation of treatment to 3 months [mean 6.8, SD 19.8; median 0.0 (range 0.0–100.0)] was significantly lower compared with the number of seizures in the 3 months prior to lacosamide initiation [mean 22.9, SD 44.5; P<0.0001; Fig. 1; median 3.0 (range 0.0–200.0)], for the 33 patients with data available after 3 months of treatment. The majority of seizures experienced in the first 3 months of lacosamide treatment were simple partial seizures followed by complex partial seizures. No patient experienced generalized seizures in the first 3 months of lacosamide treatment (Fig. 1). Similar results were observed after 6 months. Compared with the 6 months prior to lacosamide initiation, there was a significant reduction in total seizures at 6 months [prior to treatment, mean 26.4, SD 50.4, median 4.0 (range 0–200); at 6 months, mean 9.4, SD 22.8, median 0.5 (range 0–100); difference in means P<0.0001; Fig. 2].
Subsequent to 3 and 6 months of lacosamide treatment, the majority of patients exhibited a reduction in the number of seizures they experienced (72.7 and 56.5% of patients, respectively), with 87.5 and 84.6% of patients experiencing a reduction in seizure frequency of ≥50%. Furthermore, at the end of the study period, 14 patients (53.8%) reported having no seizures during treatment.
At 3 months, only 5 patients (15.2%) demonstrated no reduction in their seizure frequency following lacosamide initiation, and 4 patients (12.1%) had an increase in seizure frequency. Of these 9 patients who did not respond to lacosamide therapy, 3 were revealed to have cancer progression. Overall, 10 patients were considered to have disease progression during the study, the 7 patients who succumbed to the cancer and aforementioned 3 patients.
Finally, during the study, 10 patients experienced status epilepticus (7 convulsive and 3 non-convulsive) and were treated with levetiracetam (n=6), lacosamide (n=4), valproic acid (n=6) phenytoin (n=3) and clonazepam (n=1).
In the subgroup analysis, the mean number of seizures following 3 months of lacosamide treatment (mean 8.9, SD 22.5) was significantly lower compared with the mean number of seizures at the baseline (mean 27.4, SD 49.1; P<0001). The median number of seizures at 3 months was 2.0 (range 0.0–100.0) vs. 6.0 (range 0.0–200.0) at baseline. The majority of seizures experienced subsequent to 3 months of treatment were partial seizures followed by partial complex seizures. No generalized seizures were reported at 3 months subsequent to lacosamide treatment. After 3 months of lacosamide treatment, 80% of patients exhibited a decrease in the number of seizures, with >50% of reduction observed in 85% of these patients. Similarly, after 6 months of lacosamide treatment, the number of seizures (mean 12.2, SD 26.6) was lower compared with those reported at baseline (mean 32.9, SD 56.8; P=0.0004). The median number of seizures at 6 months was 0.0 (range 0.0–100.0) vs. 6.5 (range 0.0–200.0) at baseline. In addition, after 6 months of treatment, 68.75% of patients exhibited a reduction in the number of seizures, with 81.82% of these patients reporting a >50% reduction.
Safety
Lacosamide was generally well tolerated. Of the 25 patients who had complete safety data available at the 6-month follow-up, 3 patients (12%) reported an AE, including dizziness (n=1), asthenia (n=2), instability (n=1), irritability (n=1) and leg edema (n=1). None of these events were considered severe. No neurocognitive deficits, cardiac adverse effects or liver function test abnormalities were reported with the lacosamide treatment. Furthermore, no AEs were reported that were considered to be associated with anticancer-treatment. The subgroup analysis also demonstrated that lacosamide treatment was well tolerated over the 6-month treatment period.
Discussion
This non-interventional, observational retrospective analysis investigated the effectiveness and safety of lacosamide for the treatment of epileptic seizures due to brain tumors. The findings demonstrated that lacosamide significantly reduced the total number of seizures and was well tolerated in this patient population.
In the present study, lacosamide significantly reduced the mean number of seizures experienced over a 6-month period by a mean of 18.1 events. A large majority of patients in the current study had a reduction in the number of seizures they experienced, with 84.6% of patients experiencing a reduction in seizure frequency of ≥50% after 6 months of lacosamide treatment. Furthermore, at the end of the study period, 14 patients (40.0%) reported having no seizures whilst receiving lacosamide treatment. These efficacy results are consistent with those of clinical trials of lacosamide in patients with epilepsy, which previously demonstrated that lacosamide effectively reduces seizure frequency compared with a placebo (16–18,21). It is noteworthy that the 50% responder rate observed in this study was larger compared with those reported in the major phase III trials of lacosamide (33–41.2% of patients), despite larger doses of lacosamide administered in the phase III trials. However, it is important to note that the patients included in the phase III trials were more refractory to treatment (with a mean duration of epilepsy of 23 years) compared with the patients included in the present study.
In the present study, lacosamide was generally well tolerated, with only 3 patients (12%) reporting an AE over the 6-month treatment period. The AEs reported in this study included dizziness, asthenia, instability, irritability and leg edema. These results are consistent with clinical trials of lacosamide in patients with epilepsy, which indicated that the most common AEs associated with lacosamide involve the nervous or gastrointestinal systems, and include dizziness, headache, fatigue, nausea and diplopia (16–18,22,23). The present study had a lower frequency of AEs compared with that reported in clinical trials (range, 70–80% of patients who received 200 or 400 mg of lacosamide/day) (22,23); however, the smaller number of patients may explain this. Notably, none of the neurocognitive deficits typically associated with the use of AEDs in patients with brain tumors were reported (24). Furthermore, no cardiac adverse effects or liver function test abnormalities were reported following lacosamide treatment.
To the best of our knowledge, only a limited number of other studies have investigated the efficacy and safety of lacosamide in a similar patient population (19,25). The findings of the present study are in accordance with the results of the retrospective analysis conducted by Saria et al (19), which investigated the efficacy and safety of lacosamide as an add-on AED in 70 patients with primary brain tumors who received lacosamide for seizure activity. Similar to the present study, Saria et al (19) demonstrated that lacosamide was effective and reduced the frequency of seizures in ~66% of patients; lacosamide was additionally demonstrated to be well tolerated, with 77% of patients in the study reporting no toxicity (19). Maschio et al (25) published a preliminary report of the efficacy and tolerability of lacosamide as an add-on therapy in 14 patients with brain tumor-associated epilepsy. The results from the present study were consistent with the findings of Maschio et al, which indicated that lacosamide was effective and well tolerated (25). Therefore, in the present patient population, lacosamide may provide a valid alternative to other AEDs as an add-on therapy.
In patients with epilepsy due to brain tumors, the ideal AED would provide complete seizure control while avoiding significant AEs and drug-drug interactions, particularly as patients with brain tumors are often receiving treatments for their cancer and experiencing chemotherapy-associated AEs (2). However, there is a high risk of drug-drug interactions between anticancer agents and AEDs, particularly when using traditional enzyme-inducing AEDs (26). However, since the advent of second- and third-generation AEDs, a number of newer AEDs have demonstrated reduced drug-drug interactions, including lacosamide, gabapentin, levetiracetam and pregabalin (27). Based on the reported interactions of lacosamide with AEDs and other drugs, and its pharmacokinetic profile, we hypothesize that lacosamide may be an ideal anticonvulsant for patients with brain tumors. The results of the present study support this hypothesis, particularly as no serious drug interactions were observed during the follow-up period.
There are a number of restrictions to the present study, including the inherent limitations of the retrospective, non-controlled study design. Due to the small sample size, the confidence intervals around the point estimates obtained were correspondingly large. Also, the effect of tumor status and concomitant tumor treatment on the reduction in the number of seizures during 6 months of lacosamide treatment cannot be ruled out. As aforementioned, the efficacy and tolerability of lacosamide has been well established in a large group of patients with partial-onset seizures enrolled in three, randomized, multicenter placebo-controlled clinical trials (16–18). However, little information on the use of lacosamide in patients with brain cancer is available; thus, the present study was designed to clarify the efficacy and safety of lacosamide in this group of patients. While this is a retrospective study without a control group, data obtained in this analysis provides useful information on the efficacy and tolerability of lacosamide in patients with a high level of morbidity that are receiving multiple drugs and are thus susceptible to drug-interaction complications.
In conclusion, epilepsy is an important risk factor for long-term disability in patients with brain tumors. The present retrospective analysis suggests that lacosamide is an effective and well-tolerated treatment for patients with brain tumors who experience seizures, and additional prospective studies with a larger patient population and randomized trial design are warranted.
Acknowledgements
The authors would like to thank Ms. Ana Gentil (Pertica, Castellón, Spain) for performing the statistical analysis and Ms. Simone Boniface (Springer Healthcare Communications, Auckland, New Zealand), for assistance with medical writing. The present study was developed with the support of the Foundation of the Provincial Hospital of Castellón.
Glossary
Abbreviations
Abbreviations:
|
AEs |
adverse events |
|
AEDs |
antiepileptic drugs |
|
SD |
standard deviation |
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