Abstract
A Prospective Randomized Trial of Perioperative Seizure Prophylaxis in Patients with Intraparenchymal Brain Tumors
Wu AS, Trinh VT, Suki D, Graham S, Forman A, Weinberg JS, McCutcheon IE, Prabhu SS, Heimberger AB, Sawaya R, Wang X, Qiao W, Hess KR, Lang FF. J Neurosurg 2013;118:873–83.
OBJECT: Seizures are a potentially devastating complication of resection of brain tumors. Consequently, many neurosurgeons administer prophylactic antiepileptic drugs (AEDs) in the perioperative period. However, it is currently unclear whether perioperative AEDs should be routinely administered to patients with brain tumors who have never had a seizure. Therefore, the authors conducted a prospective, randomized trial examining the use of phenytoin for postoperative seizure prophylaxis in patients undergoing resection for supratentorial brain metastases or gliomas. METHODS: Patients with brain tumors (metastases or gliomas) who did not have seizures and who were undergoing craniotomy for tumor resection were randomized to receive either phenytoin for 7 days after tumor resection (prophylaxis group) or no seizure prophylaxis (observation group). Phenytoin levels were monitored daily. Primary outcomes were seizures and adverse events. Using an estimated seizure incidence of 30% in the observation arm and 10% in the prophylaxis arm, a Type I error of 0.05 and a Type II error of 0.20, a target accrual of 142 patients (71 per arm) was planned. RESULTS: The trial was closed before completion of accrual because Bayesian predictive probability analyses performed by an independent data monitoring committee indicated a probability of 0.003 that at the end of the study prophylaxis would prove superior to observation and a probability of 0.997 that there would be insufficient evidence at the end of the trial to choose either arm as superior. At the time of trial closure, 123 patients (77 metastases and 46 gliomas) were randomized, with 62 receiving 7-day phenytoin (prophylaxis group) and 61 receiving no prophylaxis (observation group). The incidence of all seizures was 18% in the observation group and 24% in the prophylaxis group (p = 0.51). Importantly, the incidence of early seizures (< 30 days after surgery) was 8% in the observation group compared with 10% in the prophylaxis group (p = 1.0). Likewise, the incidence of clinically significant early seizures was 3% in the observation group and 2% in the prophylaxis group (p = 0.62). The prophylaxis group experienced significantly more adverse events (18% vs 0%, p < 0.01). Therapeutic phenytoin levels were maintained in 80% of patients. CONCLUSIONS: The incidence of seizures after surgery for brain tumors is low (8% [95% CI 3%–18%]) even without prophylactic AEDs, and the incidence of clinically significant seizures is even lower (3%). In contrast, routine phenytoin administration is associated with significant drug-related morbidity. Although the lower-than-anticipated incidence of seizures in the control group significantly limited the power of the study, the low baseline rate of perioperative seizures in patients with brain tumors raises concerns about the routine use of prophylactic phenytoin in this patient population.
Commentary
Seizures constitute very serious complications of brain tumor surgery as they often delay recovery and even cause death. Seizures occur in 20 to 40 percent of patients with brain tumors (1, 2). Frontal and parietal tumor location is more likely to be associated with seizures, as are slowly growing tumors (3). Craniotomies or biopsies, often done for diagnoses, may also increase risk of seizures. Previous retrospective studies reported no significant reduction of seizure incidence with prophylactic antiepileptic medications in patients with supratentorial gliomas (4) and provided conflicting results on the role of seizure prophylaxis in patients with metastatic brain tumors (1). On the other hand, prospective studies have not specifically recruited patients with gliomas or metastatic supratentorial tumors needing craniotomy to study the efficacy of antiepileptic drug (AED) prophylaxis in reducing postoperative seizures. Such studies either focused on brain tumor patients with or without craniotomy (2), or on craniotomy patients with or without brain tumors (5). Thus, the debate continues about seizure prophylaxis after craniotomy for intraparenchymal tumor resection.
Wu et al. conducted a prospective randomized trial in patients with intraparenchymal brain tumors undergoing craniotomy to examine the use of phenytoin for postoperative seizure prevention (6). Eligible patients were ones with primary or metastatic supratentorial brain tumors who had not had seizures prior to surgery. They were randomized to a 7-day phenytoin therapy versus observation without AED treatment, and the endpoints were seizure occurrence and adverse reactions to phenytoin. Subjects in the treatment arm received intravenous loading with 15 mg/Kg of phenytoin in the operating room right before craniotomy, and were started on 100 mg every 8 hours orally or intravenously, with adjustments as needed to keep serum levels between 10 and 20 mg/L.
The study was done over 6 years at a single center. Initially, the power analysis estimated 142 patients divided equally over treatment and control arms would be needed to detect a significant (Type I error of 0.05) seizure reduction of two-thirds from an estimated seizure incidence of 30% in the observation arm to 10% in the treatment arm. The trial, however, was closed after recruiting 123 subjects—that is, 9 subjects short of the target—because a predictive probability analysis concluded that continued accrual will find no difference in seizure incidence between treatment and control arms. This was due to the low incidence of seizures in the control arm: Only 8% had seizures in the first month, compared with 10% in the phenytoin group (p = 1.0). Over the whole observation period, seizure incidence was 18% in the observation group and 24% in the phenytoin group (p = 0.51). There was also no difference in the incidence of clinically significant early seizures between the 2 groups (0.62), but the phenytoin group experienced more adverse events than controls (p < 0.01), as expected.
The findings of this study are consistent with previous randomized trials of prophylactic AEDs in patients with brain tumors that found no benefit of prophylaxis in preventing seizures (1, 2). There are many strengths in this study: First, it might be the only prospective randomized clinical trial to address the question of prophylactic antiepileptic therapy in patients undergoing craniotomy for brain tumors without a history of previous seizures. Second, the randomization was optimal as the 2 arms of the study were very adequately comparable in terms of the tumor site, functional location, tumor size, number of lesions, extent of resection, and demographic variables. A very important finding in the current study was the lower seizure incidence in the observation group than previously expected, as other studies had reported up to 40% chance of seizures in patients with brain tumors (2). Phenytoin withdrawal is unlikely to have resulted in increased seizures in the treatment arm, although a trend could be seen toward that effect: During the latter 3 weeks of the first month—which included the taper (one week) and discontinuation (2 weeks) of phenytoin—4 patients in the phenytoin arm had seizures compared with none in the observation group (p = 0.12, Fisher's exact test).
Levetiracetam and other antiepileptic drugs that do not have major interactions with other medications and have more tolerable adverse event profiles would be more appropriate choices than phenytoin for future trials, especially since most AEDs probably have comparable efficacy (7). For example, in patients undergoing radiation therapy, phenytoin can increase the risk of erythema multiforme (8, 9), which resulted in an exclusion criteria in the current study. In addition, phenytoin requires frequent serum level assessments, it is prone to interact with other medications, notably chemotherapeutic agents and antibiotics, and it has a high incidence of adverse events. In the current study, for example, a total of 20 adverse events occurred in 61 patients, including 5 major adverse events. Thus, future trials should use AEDs that are also available in intravenous and oral formulations but have better adverse event profile, linear pharmacokinetics, no interactions with other drugs, rapid onset of action, are renally excreted, and 100% bioavailable. In addition, phenytoin is not as safe for the fetus during pregnancy as levetiracetam (10). Moreover, if future studies are to assess the antiepileptogenic potential of seizure prophylaxis (by administering them shortly after craniotomy and then assessing whether seizure incidence is reduced upon longitudinal follow up after AED discontinuation), then the appropriate treatment duration that results in the best outcome should also be identified.