Levetiracetam Monotherapy in Patients with Brain Tumor-Related Epilepsy (BTRE)

Levetiracetam Monotherapy in Patients with Brain Tumor-Related (BTRE) Impact on Seizure Control and Quality of Life

Introduction

Secondary seizures for patients with brain tumor-related epilepsy (BTRE) present challenge to neurologists for many reasons. There are issues concerning the efficacy of antiepileptic drugs (AEDs) in this particular patient population. It has been observed that first-line AEDs are not effective in about 60% of patients; moreover, in these patients a similar proportion of second-line treatments with monotherapy or polytherapy are also unsuccessful. According to the study, treatment of these patients with the newer AEDs (oxcarbazepine and topiramate as monotherapy and gabapentin, pregabalin, tiagabine, and zonisamide as add on) indicates the percentage of complete seizure control to be between 27.4% and 88.9%. Previous studies on levetiracetam, as add-on and monotherapy, indicate a complete seizure control percentage of between 47.4% and 88.9%.

Several factors and conditions have to be kept in mind when considering an AED for this patient population. The safety and adverse effect profile of a drug is an important factor affecting the choice of an AED. Data on new AEDs report a percentage of side-effects ranging from 7% to 44.4%.

Another factor to be taken into consideration in patients with BTRE is the possible interaction of AEDs with systemic therapies, and vice-a-versa. It is well known in literature that older AEDs could affect the efficacy of oncological therapies through the modification of their hepatic metabolism.

Taking into consideration the available data, it is recommended to choose AEDs that do not modify hepatic metabolism, with particular attention being given to levetiracetam. Another important aspect is the impact that seizures have on the quality of life (QoL) of these patients.

This case series analysis evaluates the effects of levetiracetam treatment in monotherapy, both as first monotherapy and converted from other AEDs, on seizure control, adverse events, cognitive functioning and QoL. Also, the impact of systemic therapies [chemotherapy (CT)/ radiotherapy (RT)] on levetiracetam was evaluated.

Patient Population, Study Design and Treatment Given

The study included 29 patients with BTRE (13 female, 16 male; mean age 55 years, range 24-75 years). Patients eligible were: 1) those with simple or partial seizures, with or without secondary generalization; 2) those who had had at least 2 seizures per month prior to joining this analysis; 3) those who had never undergone prior AED therapy; 3) those who had received previous AED (verification that the previous AEDs had been in the therapeutic range); and, 4) severe side- effects with previous AED therapy.

At baseline, eligible patients underwent a complete physical and neurological examination, QoL tests, global neurocognitive evaluation, and haematological, blood chemistry and AED plasma levels.

The monthly seizure frequency (SF) in the last 2 months was also assessed based on entries in daily seizure diaries made by the patients or their relatives.

Spontaneously reported or observed side effects were recorded along with details of the time and intensity. The severity of AED side-effects was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE).

Patients not on any other AED were started on levetiracetam monotherapy as a first choice (n = 8) at a starting dose of 250 mg b.i.d, and was up-titrated (500 mg/week) to 1000- 3000 mg/day, depending upon the seizure control and tolerability.

Patients were converted from previous AED therapy to levetiracetam monotherapy due to uncontrolled seizures (n = 5) and/or side-effects (n = 16). Previous AEDs to be withdrawn were gradually tapered over a period of 3 weeks, starting at week 1 of levetiracetam treatment.

At final follow-up (12 months or last follow-up available), patients underwent QoL tests and complete physical, neurological, and hematological examinations.

The European Organization for Research and Treatment of Cancer Quality of Life Questioning-C30 (EORTC QLQ-C30) and the Quality of Life in Epilepsy- 31 for patients (QOLIE- 31-P) were the instruments used to self-assess the QoL neuropsychological functions. Brain magnetic resonance imaging (MRI) was used for tumour evaluation every 3 months.

The cognitive global profile was also evaluated by means of a Mini Mental State Examination (MMSE). Autonomy of the patients in everyday life and disability were evaluated by means of the Karnofsky Performance Status (KPS) and Barthel Index (BI). The McNemar test or Fisher's exact test were used to compare presence of seizures at baseline and follow-up, according to the groups compared (paired or independent).

Statistical analyses were performed on patients with complete follow-up (12 months). Moreover, intention-to-treat (ITT) analysis was executed on patients who had taken at least one dose of levetiracetam with seizure counts.

Result

Seizure Control

Among the patients who reached the final follow-up of 12 months (n = 15), 1 patient had a reduction of seizure frequency (SF) >50% (6.7%), and 14/15 (93.3%) were seizure free. The difference in the presence / absence of seizures between baseline and final follow-up calculated using the McNemar test was significant (p<0.001). The responder rate was 100%.

Among the ITT population (n = 29; mean duration of follow-up, 8.6 months), 21 patients were seizure free (72.4%), 7 patients had improvement in seizure frequency (SF) >50% (24.1%), and 1 had stationary SF (3.5%). The difference in the presence/ absence of seizures between baseline and final follow-up, as calculated by the McNemar test in the ITT population was significant (p<0.001). The responder rate in the ITT population was 96.6%.

The statistical analysis performed to evaluate if the seizure outcome differed between the group that completed the full 12 months of follow-up on levetiracetam and the smaller cohort of patients who died from tumor progression showed that there were significantly more patients with seizure freedom in the group that completed the full 12 months of follow-up (p = 0.007).

Side Effect

During levetiracetam monotherapy treatment, five side- effects (17.2%) were observed. Four were mild and reversible (two incidences of somnolence and two of restlessness, CTCAE grade 1) and one (restlessness) was severe enough to discontinue treatment (CTCAE grade 3).

The statistical analysis performed to evaluate if the appearance of side-effects differed between the group that completed the full 12 months of follow-up on levetiracetam and the smaller cohort of patients who died from tumor progression showed no significant differences (p = 0.062).

Hematological Parameters

The 15 patients who reached the 12-month follow-up demonstrated no statistically significant differences in hematological parameters between baseline and final follow- up (white cells, p = 0.63; red cells, p = 0.75; blood platelets, p = 0.82; hemoglobin, p = 0.75; neutrophil, p = 0.3). In the ITT population analysis (29 patients), there were also no statistically significant differences between baseline and last available follow-up (white cells, p = 0.85; red cells, p = 0.99; blood platelets, p = 0.85; hemoglobin, p = 0.97; neutrophil, p = 0.87).

Statistical analysis did not show any difference in the impact of chemotherapy on the haematological parameters both in the ITT population & the group that completed 12 months of follow-up on levetiracetam.

Systemic Treatments and Seizure Control

Logistic regression revealed that CT and RT did not affect the efficacy of levetiracetam in seizure outcome (p = 0.999), neither in the ITT population (29 patients) nor in patients with 12 months of follow-up (15 patients).

QoL and Neuropsychological Tests

The following were observed in the 15 patients who had a 12-month follow-up (Table 1)

Quality of Life in Cancer (EORTC-QLQ-C30): no significant difference.
Quality of Life in Epilepsy (QOLIE-31-P): significant improvement of the subscales for Seizure Worry (p = 0.028), Social Function (p = 0.008) and Medication Effect (p = 0.037) and significant decrease in the distress scores related to Seizure Worry and to the QoL (p = 0.004, p = 0.045).
Adverse Event Profile (AEP) related to AEDs: scores decreased significantly (p = 0.02).
Global neurocognitive performance: significant worsening of MMSE scores (p = 0.007) (mean scores remained in normal ranges).
Tests related to autonomy in everyday living and patient disability scales: significant worsening (KPS, p = 0.026; BI p = 0.044).

The following were observed in the ITT population (Table 1)

EORTC-QLQ-C30: no significant difference.
QOLIE-31-P: significant improvement of the subscales for Seizure Worry (p = 0.047), energy/ fatigue (p = 0.041), medication effect (p = 0.041), and social function (p = 0.033) and significant decrease in the distress scores related to seizure worry (p = 0.008).
Global neurocognitive performance: significant worsening of MMSE scores (p = 0.001) (mean scores remained in normal ranges).
Tests related to autonomy in everyday living and patient disability scales: significant worsening (KPS p = 0.003, BI p = 0.008).

Comparison between patients who completed the full 12 months of follow-up on levetiracetam and the smaller cohort of patients who died from tumor progression seen at baseline

No significant difference in the following: global neurocognitive performance, tests related to autonomy in everyday living and patient disability scales, EORTC-QLQ-C30, and AEP related to AEDs.
Significantly higher distress score related to social function on QOLIE-31-P in patients who died from tumor progression (p = 0.007).

At Last Follow-up

No significant difference on these parameters: global neurocognitive performance, tests related to autonomy in everyday living and patient disability scales and AEP related to AEDs.
Significantly lower scores in patients who died of tumor progression in the following subscales: Functional Scale of EORTCQLQ- C30 (p = 0.037); QOLIE- 31-P: seizure worry (p = 0.05), overall QoL (p = 0.003), emotional well-being (p = 0.010); energy/fatigue (p = 0.025); higher distress related to emotions (p = 0.031); cognitive problems (p = 0.009); and social life (p = 0.008).

Discussion

Concerning efficacy of levetiracetam on seizure control

Responder rate of 100% in patients who completed 12-month follow-up (15 patients), and 96.6% in the ITT population.
Percentage of patients seizure free of 93.3% in patients who completed the 12 months of follow-up (15 patients), and 72.4% in the ITT population.

These data are in line with data reported in the literature that demonstrate a range of complete seizure control with levetiracetam, as both add-on and monotherapy, from 47.4% to 88.9%.

Literature data concerning patients with BTRE treated with levetiracetam demonstrate an incidence of side-effects varying from 22% to 37%. In this study, the authors observed a percentage of side - effects of 17.2%, which is less than the data in the previous literature.

Some studies suggested that oncological therapies could possibly reinforce the efficacy of AEDs regarding seizure control. In this study, the authors observed that these oncological therapies (CT and RT) did not affect the efficacy of levetiracetam in a statistically significant manner.

Table 1: Result of QoL and neuropsychological test

Hematological parameters remained stable and displayed no significant differences for all of the statistical analyses performed. These data indicate that neither levetiracetam monotherapy nor CT, during the follow-up period examined, alter these hematological parameters.

In the current study, the following observations emerged (statistically significant with respect to baseline) in patients who completed the 12-month follow-up as well as in the ITT population:

Less worry about seizures, the effects of AEDs and the ability to maintain social functions;
Distress scores related to the subscales of QOLIE-31-P: seizure worry improved at final follow-up.

The authors observed an improvement of distress related to QoL only in patients who completed the 12-month follow-up, whereas in the ITT population there was an improvement in the Energy/ Fatigue subscale.

Conclusion

Results indicated that levetiracetam is a safe and effective AED, with a positive impact on quality of life in patients with BTRE.

Reference

J Neurooncol. 2011 Aug;104(1):205- 14. Epub 2010 Nov 25

Switching Patients from Phenytoin to Levetiracetam Monotherapy is Safe Following Craniotomy for Supratentorial Glioma

Introduction

Approximately 20-40% of all brain tumor patients will have a seizure. Surgical treatment of brain tumors is also associated with high risk of postoperative seizures. Phenytoin is frequently used to control tumor related seizures after craniotomy. However, phenytoin has many undesirable side effects and drug interactions with glioma chemotherapy.

Levetiracetam is a newer antiepileptic drug (AED) that possesses a different pharmacological profile from that of phenytoin; with no effects on liver enzymes and no known effect on the kinetics of other medications. Therefore, the authors prospectively studied the safety and feasibility of converting phenytoin to levetiracetam monotherapy after craniotomy for glioma resection in patients with a history of tumour-related seizures.

Patient Population, Study Design and Treatment Given
In this study, 29 patients with a history of tumor-related seizures (attributable to supratentorial glioma) and on phenytoin monotherapy for seizure prophylaxis, and planned craniotomy as standard management, were enrolled over a 13-month period. All patients were first stratified into two groups including those with no prior craniotomy, and those with a history of one craniotomy. Within each stratification group, patients were randomized in a 2:1 ratio to initiate levetiracetam therapy within 24 hour of surgery or to continue phenytoin monotherapy, respectively.

Patients were to be followed postoperatively for 6 months, during which their medical charts were reviewed and two standardized telephone surveys were conducted at ~3-month intervals. Patients were provided with seizure diaries and a 24- hour pager number to alert study personnel of any seizures or AED-related side effects. The primary end point was the proportion of patients who were seizure free 6 months after tumor resection.

Table 2: Postoperative seizure status at 6 months

Results

Altogether, 15 patients in the levetiracetam group and 8 patients in the phenytoin group were assessed for the primary end point of seizure-freedom at 6 months (Table 2). Compared with 6 phenytoin patients (75%), 13% levetiracetam patients (87%) were free. During the study period, all patients with follow-up were at least Engel Class 2 (rare seizures). Of the 2 patients who experienced rare seizures in the levetiracetam group, 1 patient had stopped taking levetiracetam, and this patient did not suffer additional seizures after resuming therapy; the other patient achieved seizure control with an increased dosage of levetiracetam (1,500 mg twice a day). Most (11/15) levetiracetam patients remained on the initial dose of 1,000 mg twice a day; 3 levetiracetam patients were able to lower their dosage to 500 mg twice a day without compromising their complete seizure control. Phenytoin dosages were between 300 and 400 mg per day given as single dose. No patient required hospitalization for seizures or seizure control.

Reported side-effects at 6 months were as follows (%levetiracetam /% phenytoin group): dizziness (0/14), difficulty with coordination (0/29), depression (7/14) lack of energy or strength (20/43), insomnia (40/43) and mood instability (7/0). The patient who was taking levetiracetam 1,500 mg twice a day did not report more side effects than those taking 500 mg twice a day, suggesting that levetiracetam dosage does not correlate with increased side effects.

Discussion

An ideal AED for brain tumor patients would be one that has few side effects and does not interfere with medications commonly used in brain tumor treatment. While phenytoin is very commonly used for seizure control in brain tumor patients, it has many undesirable pharmacological qualities. Because levetiracetam does not have any significant drug interactions, this AED poses fewer complications for the pharmacotherapy of brain tumors.

In this study population, the levetiracetam and phenytoin groups had similar proportions of seizure-free patients (87% and 75%, respectively) at 6 months of follow-up. These seizure control rates are in line with those observed in a retrospective analysis of low grade glioma patients. Out of 253 patients who had tumor-related seizures, 169 (67%) were seizure-free, 6 months after craniotomy for tumor resection. Thus, the levetiracetam and phenytoin groups had expected levels of seizure control. In addition, no patient in the current study had seizures refractory to either levetiracetam or phenytoin therapy.

Levetiracetam and phenytoin were both well tolerated in the study population. Although difficulty with coordination is a potential side effect for both levetiracetam and phenytoin, no patient in the levetiracetam study group (0/15) admitted to experiencing this difficulty while more than half of the phenytoin group (4/7) at 3 months reported this side effect. Other known levetiracetam side effects are somnolence and behavioral abnormalities.

Both the phenytoin and levetiracetam groups had similar proportions of patients reporting somnolence. One subject in the levetiracetam group reported feeling unusually hostile towards others after starting levetiracetam therapy. However, this behavioral change did not require the discontinuation of levetiracetam. No phenytoin study subject admitted to experiencing any emotional instability at any time point.

Conclusion

In a nutshell, it is safe and feasible to switch from phenytoin to levetiracetam monotherapy after craniotomy for glioma-related seizures.

Reference

J Neurooncol. 2009 Jul; 93(3):349-54. Epub 2009 Jan 24

Levetiracetam is Considerably Better Tolerated than Phenytoin

Introduction

Neurosurgeons have considered patients to be at significant risk for seizures after supratentorial surgery (especially, following surgeries for brain tumors and traumatic brain injury), although the actual risk is highly variable and only in the range of about 3%. Therefore, it has been a common practice to provide phenytoin as seizure prophylaxis after neurosurgery. However, phenytoin commonly causes side effects that are annoying and, may also cause serious reactions, including anticonvulsant hypersensitivity syndrome, serious rash, purple glove syndrome, and necrosis when extravasated. This retrospective study compared the use of levetiracetam and phenytoin as monotherapy prophylaxis following supratentorial neurosurgery.

Method

The authors retrospectively reviewed their experience with 105 patients who took levetiracetam and compared it with 210 patients who used phenytoin as AED prophylaxis for seizures after supratentorial craniotomy.

Results

Seizures occurred within 7 days of surgery (p = 0.17) in 1/105 patients taking levetiracetam and 9/210 patients taking phenytoin. Adverse drug reactions requiring change in therapy during hospitalization occurred in 1/105 patients taking levetiracetam and 38/210 patients taking phenytoin (p < 0.001). Among patients followed for at least 12 months, 11/42 (26%) treated with levetiracetam versus 42/117 (36%) treated with phenytoin developed epilepsy (p = 0.34); 64% remained on levetiracetam, while 26% remained on phenytoin (p = 0.03).

Discussion

Levetiracetam was better tolerated than phenytoin and seemingly equally efficacious. Thus, the findings of the authors is evidence that levetiracetam may be preferable to phenytoin. However, the study suffers from the limitations of a retrospective design: the phenytoin group had higher median age, fewer primary brain tumors, and a smaller proportion with preoperative seizures, which could have skewed the results. Despite some limitations, the study does report outcomes that are clinically useful and extends the general clinical observations that levetiracetam is better tolerated than phenytoin in the specific setting of AED prophylaxis after supratentorial craniotomy.

Conclusion

Both levetiracetam and phenytoin were associated with a low risk of early postoperative seizures and a moderate risk of later epilepsy. Levetiracetam was associated with significantly fewer early adverse reactions than phenytoin and with a higher retention rate in patients who were followed for at least 1 year and developed epilepsy.

Epilepsy Curr. 2009; 9: 71-2

Epilepsy Times - Issue 3: Levetiracetam Monotherapy in Patients with Brain Tumor Related Epilepsy (BTRE)