Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study

Daniel A. Lim 0 1 Phiroz Tarapore 0 1 Edward Chang 0 1 Marlene Burt 0 1 Lenna Chakalian 0 1 Nicholas Barbaro 0 1 Susan Chang 0 1 Kathleen R. Lamborn 0 1 Michael W. McDermott 0 1 0 D. A. Lim Surgical Service, Department of Veterans Affairs Medical Center , San Francisco, CA, USA 1 D. A. Lim P. Tarapore E. Chang M. Burt L. Chakalian N. Barbaro S. Chang K. R. Lamborn M. W. McDermott (&) Department of Neurological Surgery, University of California , 505 Parnassus Ave. M779, San Francisco, CA 94143, USA Seizures are common in patients with gliomas, and phenytoin (PHT) is frequently used to control tumorrelated seizures. PHT, however, has many undesirable side effects (SEs) and drug interactions with glioma chemotherapy. Levetiracetam (LEV) is a newer antiepileptic drug (AED) with fewer SEs and essentially no drug interactions. We performed a pilot study testing the safety and feasibility of switching patients from PHT to LEV monotherapy for postoperative control of glioma-related seizures. Over a 13-month period, 29 patients were randomized in a 2:1 ratio to initiate LEV therapy within 24 h of surgery or to continue PHT therapy. 6 month follow-up data were available for 15 patients taking LEV and for 8 patients taking PHT. In the LEV group, 13 patients (87%) were seizure-free. In the PHT group, 6 patients (75%) were seizure-free. Reported SEs at 6 months was as follows (%LEV/%PHT group): dizziness (0/14), difficulty with coordination (0/29), depression (7/14) lack of energy or strength (20/43), insomnia (40/43), mood instability (7/0). The pilot data presented here suggest that it is safe to switch patients from PHT to LEV monotherapy following craniotomy for supratentorial glioma. A large-scale, double-blinded, randomized control trial of LEV versus PHT is required to determine seizure control equivalence and better assess differences in SEs. - At diagnosis, *2040% of all brain tumor patients will have had a seizure [1] that may result in morbidity and decreased quality of life [2]. Thus, treatment with antiepileptic drugs (AEDs) is clearly indicated for brain tumor patients with preoperative tumor-related seizures [35]. Surgical treatment of brain tumors is also associated with a high risk of postoperative seizures. Approximately, onethird of patients have seizures after tumor resection [68], and in the case of supratentorial craniotomy, 20%50% of patients have C1 seizure [9, 10]. Brain tumor patients who experience tumor-related seizures are often placed on phenytoin (PHT) therapy. Although there are no formal guidelines, it is common practice to continue PHT after craniotomy in these patients. However, PHT has many side effects (SEs) and undesirable interactions with drugs used to treat brain tumors [1, 11 14] which can complicate the pharmacological treatment of these tumors. Levetiracetam (LEV) is a newer AED that possesses a different pharmacological profile from that of PHT, with no effects on liver enzymes and no known effect on the kinetics of other medications [15, 16]. Furthermore, other medications including enzyme-inducing AEDs have essentially no effect on LEV pharmacokinetics [15, 17]. In retrospective studies, LEV has been found to be effective and well tolerated as add-on or monotherapy in patients with either primary or metastatic brain tumors [18, 19]. Prospectively, LEV has been studied mostly as add-on therapy for persistent tumor-related seizures [20, 21], and for this purpose, LEV appears to be safe and feasible and with few SEs. Ideally, patients with brain tumor-related seizures would achieve seizure control with an AED that does not negatively interact with adjunctive chemotherapy and has few SEs. However, PHT is still commonly used as a first-line AED in brain tumor patients, and conversion of PHT therapy to LEV monotherapy has not been studied. Therefore, we prospectively studied the safety and feasibility of converting PHT to LEV monotherapy after craniotomy for glioma resection in patients with a history of tumor-related seizures. Materials and methods Key patient inclusion criteria for the study included: seizure history attributable to supratentorial glioma, PHT monotherapy for seizure prophylaxis, planned craniotomy as standard management, B1 previous resection, [18 years of age, Karnofosky performance scale of [70, and no other co-morbidities. Exclusion criteria included: non-glioma cancer, pregnancy or breast-feeding, seizures unrelated to the suspected glioma, use of anticonvulsants or AEDs other than PHT, [1 generalized seizure per day, and prior interstitial brachytherapy. Preoperative labs were examined to ensure that patients had a WBC [3.4 9 109/l, platelets [100,000/l, hemoglobin [10 g/dl, INR \1.3, and serum creatinine \1.5 mg/dl. We had planned to enroll 60 patients in this study (40 patients in the LEV group, 20 in the PHT group). This study was designed to be a feasibility study for a potential larger trial. We designed this trial to have met the feasibility requirement if seizure control was no more than 20% points worse than historical controls. Because of a diminishing accrual rate, we closed the study after the enrollment of 29 patients. These 29 patients were enrolled over a 13-month period. After signing an approved Institutional Review Board consent form, patients were first stratified into two groups: (1) those with no prior craniotomy, and (2) those with a history of one craniotomy. Within each stratification group, patients were randomized in a 2:1 ratio to initiate LEV therapy within 24 h of surgery or to continue PHT therapy, respectively (Fig. 1). Patients randomized to PHT therapy had serum levels confirmed to be in the therapeutic range (1020 mg/dl) by the first postoperative day (POD1); PHT dosages were adjusted, if necessary. Patient randomized to LEV therapy were started on an oral regimen of LEV 1,000 mg twice a day within 24 h of surgery; in these patients, PHT was tapered off in the following manner: 100% of preoperative PHT regimen on POD0, 75% of PHT regimen on POD1, 50% of PHT regimen on POD2, and PHT therapy was discontinued on POD3. 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-h pager number to alert study personnel of any seizures or AED-related SEs. Seizure frequency data were based on patient-initiated contact of study personnel (through use of the 24-h pager), the telephone surveys, and review of medical charts. The primary end point was the proportion of patients who were seizure free 6 months after tumor resection. Data on AED-related SEs were collected with use of the telephone survey specifically addressing the SEs listed in Table 3. Characteristics of the study population are summarized in Table 1. Although there were some demographic differences between the two treatment groups, the majo (...truncated)