Seizure prophylaxis with valproic acid in pediatric patients with braintumors

Francisco Hélder Cavalcante Félix2, Igor Moreira Veras3, CletoDantas Nogueira4, Jony Arrais Pinto Junior5, Orlandira Leitede Araújo2, Nádia Mendonça Trompieri2, Juvenia Bezerra

Fontenele11 - Curso de Farmácia, Faculdade de Farmácia Odontologia e Enfermagem, Universidade Federal do Ceará

2 - Hospital Infantil Albert Sabin, Secretaria de Saúde do Estado do Ceará3 - CRIO - Centro Regional Integrado de Oncologia4 - Argos Patologia e Faculdade de Medicina da UFC

5 - Departamento de Estatística - Universidade Federal Fluminensehelder.felix@hias.ce.gov.br

XIV Congresso Brasileiro de Oncologia Pediátrica — SOBOPE 2014

Introduction

Valproic acid (valproate sodium, VPA) is an anti-epileptic drug (AED) widely used for treating sei-

zures in children. It has also been used for seizures asso-ciated with brain tumors [1]. Seizure prophylaxis is con-troversial in brain tumor patients. However, a recent me-tanalysis was not conclusive due to the lack of appropriateclinical data [2]. Seizures are more frequent in pediatricpatients with a supratentorial tumor but can nonethelessinfrequently occur in posterior fossa tumor patients, andtheir determinants have remained obscure[1]. In our cen-ter, we deal with patients that have inadequate access tomedical services, and there have been occasional episodesof seizures in children with posterior fossa brain tumorunder our care. Based on these local differences, we con-sidered using prophylactic AED administration to all pe-diatric patients with brain tumors. After the beginning ofprophylactic administration we observed a trend towardslonger survival in a subset of our patients. In order tostudy the possible influence of valproate in the survivalof pediatric patients with brain tumors we have underta-ken a retrospective cohort study. We also compared thiscohort with a historical control from our institution. Dueto modifications in referral policies in our state, the admis-sion rate of new patients in our center more than doubledfrom before 2007 to nowadays. [3].

MethodsThe institutional review board of our center approved this re-

trospective study. We reviewed the charts of patients referred to ourinstitution and diagnosed between January 2000 and December 2008with primary brain tumors, aged 0–17 years. A member of our teamreviewed magnetic resonance images (MRI) for tumor site and cha-racteristics. Some of the images from patients diagnosed before 2006were not available for review, so we used the description of the radi-ological report to classify the tumors. Usual image parameters (Mac-Donald’s criteria) were used to analyze MRI and judge disease pro-gression [4]. The primary study endpoint for treatment efficacy wastime to death due to any cause, from which overall survival (OS) wascomputed. The primary objective of the statistical analysis was todetermine whether the valproate treatment produced a difference inthe median overall survival. Survival functions were fitted with theKaplan-Meyer method [5] and compared with log rank test, expres-sing the results as hazard ratios (HRs) with 95% confidence intervals(CIs). We then performed multivariate analysis with Cox proportio-nal hazards model and the additive hazards Aalen Model to comparethe survival function of groups, adjusting for demographic, biomedi-cal, imaging, disease, and treatment characteristics [6, 7]. We con-sidered the use of valproate as a time-dependent covariate in orderto adjust the survival model. Pearson’s chi-squared test was usedto compare the risk of new-onset seizures between treated and non-treated groups. Data descriptive statistics and statistical calculationswere performed on R 2.12 for Mac OSX (R Foundation for StatisticalComputing, 2010).

Results

Figura 1: Global survival estimates of whole cohort (Kaplan-Meier,dashedlines:±95%CI) and by covariates (Aalen model). Radiation therapy, surgicalressection, and hystological group were statistically significant (p < 0.005)

One hundred, sixty five patients were included, 70 fe-male, median age 7.4 years, 34% embryonal tumors, 19%low grade gliomas, 27% brainstem tumors. Median ove-raal survival for the whole cohort was 29 (19-36) months.Median follow-up time was 24 months. Eighty patientsreceived prophylatic VPA. Median OS of patients thatreceived prophylatic VPA was 35 months, and medianOS of non-treated patients was 15 months. Two-year OSwas 39% (29-51) for non-treated and 66% (56-78) for tre-ated patients. Cox model could not fit the data due totime-dependent variation of VPA treatment. A regressionwas adjusted with Aalen’s time-dependent model, tes-ting VPA prophylaxis influence on survival probability.Radiation therapy, surgery, and hystological group hadstatistically significant (p < 0.005) influence on survival

probability of the whole cohort of patients, but not VPAtreatment. Aalen-model estimated survival probability ofboth groups was 46% (non-treated) ans 55% (treated) at2 years and 41 and 46% at 5 years. At the end of the fol-low up time, 69 patients were alive. Twenty-one patientshad had seizures of new onset after diagnosis, 12 of themhad been treated with VPA prophylaxis. A comparisonwith Pearson’s chi-squared test yielded a non-significantdifference in new-onset seizures risk between treated andnon-treated groups.

ConclusionsValproic acid, thus, had no effect in survival pro-

bability of a heterogenous group of pediatric patientswith brain tumors. Seizure prophylaxis with VPA for thiscohort of patients was apparently ineffective, so it shouldnot be routinely used for children with brain tumors.

References[1] WELLS EM, Gaillard WD, Packer RJ Pediatric brain tumors and epilepsy.

Semin Pediatr Neurol 2012;19(1):3–8[2] TREMONT-LUKATS I, Ratilal B, Armstrong T et al Antiepi- leptic drugs

for preventing seizures in people with brain tumors. Cochrane Database SystRev 2008;16(2):CD004424

[3] FELIX FH, Trompieri NM, de Araujo OL, da Trindade KM, Fontenele JB.Potential role for valproate in the treatment of high-risk brain tumors ofchildhood-results from a retrospective observational cohort study. Pediatr He-matol Oncol 2011:28:556–570

[4] MACDONALD DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Res-ponse criteria for phase II studies of supratentorial malignant glioma. J ClinOncol 8(7):1277–1280

[5] KAPLAN EL, Meier P. Nonparametric estimationfrom incomplete observati-ons. J Amer Stat Assoc 1958;53(282):457-81.

[6] ANDERSEN, P. and Gill, R. Cox’s regression model for counting processes, alarge sample study. Annals of Statistics 1982;10:1100-1120.

[7] MARTINUSSEN and Scheike, Dynamic Regression Models for Survival Data,Springer (2006).

Aknowledgements

SOBOPE 2014 - XIV Congresso Brasileiro de Oncologia Pediátrica