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01-07-2012 | Clinical Study

Impact of antiepileptic drugs on thrombocytopenia in glioblastoma patients treated with standard chemoradiotherapy

Authors: Marta Simó, Roser Velasco, Francesc Graus, Eugenia Verger, Miguel Gil, Estela Pineda, Jaume Blasco, Jordi Bruna

Published in: Journal of Neuro-Oncology | Issue 3/2012

Abstract

Epilepsy in glioblastoma multiforme (GBM) patients is common. Hematological toxicity is a potential side effect of antiepileptic drugs (AEDs) and a frequent limiting-dose effect of temozolomide (TMZ). The aim of the study was to investigate the impact of AEDs on thrombocytopenia in GBM patients treated with radiotherapy and TMZ. A cohort of 101 newly diagnosed GBM patients treated with radiotherapy and TMZ was reviewed. Clinical data, presence of seizures, AEDs use, platelet count, and accumulated TMZ dose were analyzed at each cycle. Thrombocytopenia was operationalized as a continuous platelet count and a dichotomic variable (cut-off <100.000/mm³). This cut-off represents the threshold beyond which TMZ treatment is modified. A linear and a probit pooled cross-sectional regression analysis were used to study the impact of age, gender, AEDs, and accumulated TMZ on thrombocytopenia. Impact of AEDs on survival was also analyzed. Thirty-five patients (35%) presented seizures at onset and 18 (27%) during follow-up. Seven (13%) needed two or more AEDs for seizure control. Grade 3–4 thrombocytopenia was found in 8%. Decrease in platelet count was related to accumulated TMZ (p < 0.001), age (p < 0.001), and valproate (p = 0.004). Platelet count <100.000/mm³ was only associated with accumulated TMZ (p = 0.001). Recursive Partitioning Analysis prognostic class was the only variable with significant impact on survival. Valproate and age had an independent negative effect on total platelet count, although neither had an effect on critical thrombocytopenia (<100.000/mm³). Therefore, the systematic withhold of valproate in GBM patients might not be justified. Nevertheless, this negative effect may be taken into account especially in elderly patients.

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Wrensch M, Minn Y, Chew T, Bondy M, Berger MS (2002) Epidemiology of primary brain tumors: current concepts and review of the literature. Neuro Oncol 4:278–299PubMed

Stupp R, Mason WP, Van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRef

Gerber DE, Grossman SA, Zeltzman M, Parisi MA, Kleinberg L (2007) The impact of thrombocytopenia from temozolomide and radiation in newly diagnosed adults with high-grade gliomas. Neuro Oncol 9:47–52PubMedCrossRef

Hau P, Koch D, Hundsberger T et al (2007) Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma. Neurology 68:688–690PubMedCrossRef

Vecht CJ, Wilms EB (2010) Seizures in low- and high-grade gliomas: current management and future outlook. Expert Rev Anticancer Ther 10:663–669PubMedCrossRef

Van Breemen MS, Wilms EB, Vecht CJ (2007) Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol 6:421–430PubMedCrossRef

Vecht CJ, Van Breemen M (2006) Optimizing therapy of seizures in patients with brain tumors. Neurology 67(12 suppl 4):S10–S13PubMedCrossRef

Badyal DK, Dadhich AP (2001) Cytochrome P450 and drug interactions. Indian J Pharmacol 33:248–259

Patsalos PN, Fröscher W, Pisani F, Van Rijn CM (2002) The importance of drug interactions in epilepsy therapy. Epilepsia 43:365–385PubMedCrossRef

10.

Anderson GD (2004) Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs. Neurology 63(suppl 4):S3–S8PubMedCrossRef

11.

Vecht CJ, Wagner GL, Wilms EB (2003) Interactions between antiepileptic and chemotherapeutic drugs. Lancet Neurol 2:404–409PubMedCrossRef

12.

Vecht CJ, Wagner GL, Wilms EB (2003) Treating seizures in patients with brain tumors: drug interactions between antiepileptic and chemotherapeutic agents. Semin Oncol 30(6 suppl 19):49–52PubMedCrossRef

13.

Gajjar A, Chintagumpala MM, Bowers DC, Jones-Wallace D, Stewart CF, Crews KR (2003) Effect of intrapatient dosage escalation of irinotecan on its pharmacokinetics in pediatric patients who have high-grade gliomas and receive enzyme-inducing anticonvulsant therapy. Cancer 97(suppl 9):2374–2380PubMedCrossRef

14.

Villikka K, Kivistö KT, Mäenpää H, Joensuu H, Neuvonen PJ (1999) Cytochrome P450-inducing antiepileptics increase the clearance of vincristine in patients with brain tumors. Clin Pharmacol Ther 66:589–593PubMed

15.

Jaeckle KA, Ballman K, Furth A, Buckner JC (2009) Correlation of enzyme-inducing anticonvulsant use with outcome of patients with glioblastoma. Neurology 73:1207–1213PubMedCrossRef

16.

Oberdornfer S, Piribauer M, Marosi C, Lahrmann H, Hitzenberger P, Grisold W (2005) P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy. J Neurooncol 72:255–260CrossRef

17.

Weller M, Gorlia T, Cairncross JC et al (2011) Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology 77:1156–1164PubMedCrossRef

18.

Bourg V, Lebrun C, Chichmanian RM, Thomas P, Frenay M (2001) Nitroso-urea-cisplatin-based chemotherapy associated with valproate: increase of haematologic toxicity. Ann Oncol 12:217–219PubMedCrossRef

19.

Friedman HS, Kerby T, Calvert H (2000) Temozolomide and treatment of malignant glioma. Clin Cancer Res 6:2585–2597PubMed

20.

Blackburn SC, Oliart AD, García Rodríguez LA, Pérez Gutthann S (1998) Antiepileptics and blood dyscrasias: a cohort study. Pharmacotherapy 18:1277–1283PubMed

21.

Nasreddine W, Beydoun A (2008) Valproate-induced thrombocytopenia: a prospective monotherapy study. Epilepsia 49:438–445PubMedCrossRef

22.

Kimland E, Höjeberg B, Von Euler M (2004) Levetiracetam-induced thrombocytopenia. Epilepsia 45:877–878PubMedCrossRef

23.

Mesche A, Runge U, Sabolek M (2008) Thrombocytopenia during levetiracetam therapy. Epilepsy Res 80:91–92CrossRef

24.

Gallerani M, Mari E, Boaria B, Carletti R, Marra A, Cavallo M (2009) Pancytopenia associated with levetiracetam treatment. Clin Drug Investig 29:747–751PubMedCrossRef

25.

Elouni B, Ben Salem C, Biour M (2009) Levetiracetam-induced pancytopenia. Ann Pharmacother 43:985PubMedCrossRef

26.

Oghlakian R, Nock C, Koubeissi M (2010) A case of levetiracetam-induced thrombocytopenia. Epileptic Disord 12:335–337PubMed

27.

Sahaya K, Goyal MK, Sarwal A, Singh NN (2010) Levetiracetam-induced thrombocytopenia among inpatients: a retrospective study. Epilepsia 51:2492–2495PubMedCrossRef

28.

Scott CB, Scarantino C, Urtasun R et al (1998) Validation and predictive power of radiation therapy oncology group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90–06. Int J Radiat Oncol Biol Phys 40:51–55PubMedCrossRef

29.

Mirimanoff RO, Gorlia T, Mason W et al (2006) Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol 24:2563–2569PubMedCrossRef

30.

Chang SM, Parney IF, Huang W et al (2005) Patterns of care for adults with newly diagnosed malignant glioma. JAMA 293:557–564PubMedCrossRef

31.

Macdonald D, Cascino T, Schold SJ, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280PubMed

32.

Maschio M, Albani F, Jandolo B et al (2008) Temozolomide treatment does not affect topiramate and oxcarbazepine plasma concentrations in chronically treated patients with brain tumor-related epilepsy. J Neurooncol 90:217–221PubMedCrossRef

33.

Van Breemen M, Rijsman RM, Taphoorn MJB, Walchenbach R, Zwinkels H, Vecht CJ (2009) Efficacy of anti-epileptic drugs in patients with gliomas and seizures. J Neurol 256:1519–1526PubMedCrossRef

34.

Maschio M, Dinapoli L, Vidiri A et al (2009) The role side effects play in the choice of antiepileptic therapy in brain tumor-related epilepsy: a comparative study on traditional antiepileptic drugs versus oxcarbazepine. J Exp Clin Cancer Res 28:60PubMedCrossRef

35.

Maschio M, Dinapoli L, Saveriano F et al (2009) Efficacy and tolerability of zonisamide as add-on in brain tumor-related epilepsy: preliminary report. Acta Neurol Scand 120:210–212PubMedCrossRef

36.

Merrell RT, Anderson SK, Meyer FB, Lachance DH (2010) Seizures in patients with glioma treated with phenytoin and levetiracetam. J Neurosurg 113:1176–1181PubMedCrossRef

37.

Klotz U (2009) Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev 41:67–76PubMedCrossRef

38.

Armstrong TS, Cao Y, Scheurer ME et al (2009) Risk analysis of severe myelotoxicity with temozolomide: the effects of clinical and genetic factors. Neuro Oncol 11:825–832PubMedCrossRef

39.

Koshy M, Villano JL, Dolecek TA et al (2012) Improved survival time trends for glioblastoma using the SEER 17 population-based registries. J Neurooncol 107:207–212

40.

Vredenburgh JJ, Desjardins A, Herndon JE et al (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722–4729PubMedCrossRef

41.

Stupp R, Hegi ME, Mason WP et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466PubMedCrossRef

42.

Wen PY, Macdonald DR, Reardon DA et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972PubMedCrossRef

43.

Eyal S, Yagen B, Sobol E, Altschuler Y, Shmuel M, Bialer M (2004) The activity of antiepileptic drugs as histone deacetylase inhibitors. Epilepsia 45:737–744PubMedCrossRef

44.

Li XN, Shu Q, Su JM, Perlaky L, Blaney SM, Lau CC (2005) Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC. Mol Cancer Ther 4:1912–1922PubMedCrossRef

45.

Fu J, Shao CJ, Chen FR, Ng HK, Chen ZP (2010) Autophagy induced by valproic acid is associated with oxidative stress in glioma cell lines. Neuro Oncol 12:328–340PubMedCrossRef

46.

Chen CH, Chang YJ, Ku MS, Chung KT, Yang JT (2011) Enhancement of temozolomide-induced apoptosis by valproic acid in human glioma cell lines through redox regulation. J Mol Med 89:303–315PubMedCrossRef

47.

Bobustuc GC, Baker CH, Limaye A et al (2010) Levetiracetam enhances p53-mediates MGMT inhibition and sensitizes glioblastoma cell to temozolomide. Neuro Oncol 12:917–927PubMedCrossRef

Title: Impact of antiepileptic drugs on thrombocytopenia in glioblastoma patients treated with standard chemoradiotherapy
Authors: Marta Simó
Roser Velasco
Francesc Graus
Eugenia Verger
Miguel Gil
Estela Pineda
Jaume Blasco
Jordi Bruna
Publication date: 01-07-2012
Publisher: Springer US
Published in: Journal of Neuro-Oncology / Issue 3/2012
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-012-0836-1

At a glance: The STEP trials

Springer Medicine

Impact of antiepileptic drugs on thrombocytopenia in glioblastoma patients treated with standard chemoradiotherapy

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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