Effect of anti-epileptic drugs on the survival of patients with glioblastoma multiforme: A retrospective, single-center study


Autoři: Jae Yeoul Ryu aff001;  Kyoung Lok Min aff002;  Min Jung Chang aff001
Působiště autorů: Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Republic of Korea aff001;  Department of Pharmaceutical Medicines and Regulatory Science, Colleges of Medicine and Pharmacy, Yonsei University, Incheon, Republic of Korea aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225599

Souhrn

Glioblastoma multiforme (GBM) is a lethal and aggressive malignant tumor of the central nervous system. The World Health Organization classifies it as a grade IV astrocytoma. Controlling seizures is essential during GBM treatment because they are often present and closely associated with the quality of life of GBM patients. Some antiepileptic drugs (AEDs) exhibit antitumor effects and could decrease the mortality of patients with GBM. In this retrospective cohort study, we examined 418 patients treated with surgery, radiotherapy, and chemotherapy with temozolomide (TMZ) at Severance Hospital in South Korea, per the current protocol. Median overall survival (OS) was 21 months [95% confidence interval (CI): 18.1–23.9] in the levetiracetam (LEV) treatment group, whereas it was 16 months [95% CI: 14.1–17.9] in the group without LEV, exhibiting a statistically significant difference between the two groups (P < 0.001). Of nine AED groups, only LEV treatment [P = 0.001; hazard ratio (HR), 0.65; 95% CI: 0.51–0.83] exhibited a statistically significant difference in the OS, in the univariate analysis. In the risk analysis of the baseline characteristics, age, administration of LEV, and O6-methylguanine-DNA methyltransferase (MGMT) promoter status correlated with OS. The use of LEV in the group with a methylated MGMT promoter resulted in a positive impact on the OS [P = 0.006; HR, 0.174; 95% CI: 0.050–0.608], but the effect of LEV on the OS was not statistically significant in the unmethylated MGMT promoter group (P = 0.623). This study suggests that, compared with other AEDs, the administration of LEV may prolong the survival period in GBM patients with methylated MGMT promoters, who are undergoing chemotherapy with TMZ.

Klíčová slova:

Cancer treatment – Glioblastoma multiforme – Human genetics – Methylation – Prognosis – Radiation therapy – Surgical and invasive medical procedures – Methyltransferases


Zdroje

1. Komori T. The 2016 WHO Classification of Tumours of the Central Nervous System: The Major Points of Revision. Neurol Med Chir (Tokyo). 2017;57: 301–311. doi: 10.2176/nmc.ra.2017-0010 28592714

2. Thakkar JP, Dolecek TA, Horbinski C, Ostrom QT, Lightner DD, Barnholtz-Sloan JS, et al. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomarkers Prev. 2014;23: 1985–1996. doi: 10.1158/1055-9965.EPI-14-0275 25053711

3. Jung KW, Yoo H, Kong HJ, Won YJ, Park S, Lee SH. Population-based survival data for brain tumors in Korea. J Neurooncol. 2012;109: 301–307. doi: 10.1007/s11060-012-0893-5 22660961

4. Oike T, Suzuki Y, Sugawara K, Shirai K, Noda SE, Tamaki T, et al. Radiotherapy plus concomitant adjuvant temozolomide for glioblastoma: Japanese mono-institutional results. PLoS One. 2013;8: e78943. doi: 10.1371/journal.pone.0078943 24265731

5. Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31: 4085–4091. doi: 10.1200/JCO.2013.49.6968 24101040

6. Stupp R, Brada M, van den Bent MJ, Tonn JC, Pentheroudakis G. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25 Suppl 3: iii93–101. doi: 10.1093/annonc/mdu050 24782454

7. Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, et al. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. Jama. 2015;314: 2535–2543. doi: 10.1001/jama.2015.16669 26670971

8. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360: 765–773. doi: 10.1056/NEJMoa0808710 19228619

9. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352: 997–1003. doi: 10.1056/NEJMoa043331 15758010

10. Clark KH, Villano JL, Nikiforova MN, Hamilton RL, Horbinski C. 1p/19q testing has no significance in the workup of glioblastomas. Neuropathol Appl Neurobiol. 2013;39: 706–717. doi: 10.1111/nan.12031 23363074

11. Bobustuc GC, Baker CH, Limaye A, Jenkins WD, Pearl G, Avgeropoulos NG, et al. Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide. Neuro Oncol. 2010;12: 917–927. doi: 10.1093/neuonc/noq044 20525765

12. Ikemura M, Shibahara J, Mukasa A, Takayanagi S, Aihara K, Saito N, et al. Utility of ATRX immunohistochemistry in diagnosis of adult diffuse gliomas. Histopathology. 2016;69: 260–267. doi: 10.1111/his.12927 26741321

13. Englot DJ, Chang EF, Vecht CJ. Epilepsy and brain tumors. Handb Clin Neurol. 2016;134: 267–285. doi: 10.1016/B978-0-12-802997-8.00016-5 26948360

14. Maschio M, Dinapoli L. Patients with brain tumor-related epilepsy. J Neurooncol. 2012;109: 1–6. doi: 10.1007/s11060-012-0867-7 22528794

15. Happold C, Gorlia T, Chinot O, Gilbert MR, Nabors LB, Wick W, et al. Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma. J Clin Oncol. 2016;34: 731–739. doi: 10.1200/JCO.2015.63.6563 26786929

16. Scicchitano BM, Sorrentino S, Proietti G, Lama G, Dobrowolny G, Catizone A, et al. Levetiracetam enhances the temozolomide effect on glioblastoma stem cell proliferation and apoptosis. Cancer Cell Int. 2018;18: 136. doi: 10.1186/s12935-018-0626-8 30214378

17. Van Nifterik KA, Van den Berg J, Slotman BJ, Lafleur MV, Sminia P, Stalpers LJ. Valproic acid sensitizes human glioma cells for temozolomide and gamma-radiation. J Neurooncol. 2012;107: 61–67. doi: 10.1007/s11060-011-0725-z 22037799

18. Barker CA, Bishop AJ, Chang M, Beal K, Chan TA. Valproic acid use during radiation therapy for glioblastoma associated with improved survival. Int J Radiat Oncol Biol Phys. 2013;86: 504–509. doi: 10.1016/j.ijrobp.2013.02.012 23523186

19. Thotala D, Karvas RM, Engelbach JA, Garbow JR, Hallahan AN, DeWees TA, et al. Valproic acid enhances the efficacy of radiation therapy by protecting normal hippocampal neurons and sensitizing malignant glioblastoma cells. Oncotarget. 2015;6: 35004–35022. doi: 10.18632/oncotarget.5253 26413814

20. Yuan Y, Xiang W, Qing M, Yanhui L, Jiewen L, Yunhe M. Survival analysis for valproic acid use in adult glioblastoma multiforme: a meta-analysis of individual patient data and a systematic review. Seizure. 2014;23: 830–835. doi: 10.1016/j.seizure.2014.06.015 25066904

21. Chang CY, Li JR, Wu CC, Ou YC, Chen WY, Kuan YH, et al. Valproic acid sensitizes human glioma cells to gefitinib-induced autophagy. IUBMB Life. 2015;67: 869–879. doi: 10.1002/iub.1445 26488897

22. Hosein AN, Lim YC, Day B, Stringer B, Rose S, Head R, et al. The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells. J Neurooncol. 2015;122: 263–271. doi: 10.1007/s11060-014-1713-x 25648357

23. Krauze AV, Myrehaug SD, Chang MG, Holdford DJ, Smith S, Shih J, et al. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma. Int J Radiat Oncol Biol Phys. 2015;92: 986–992. doi: 10.1016/j.ijrobp.2015.04.038 26194676

24. Cardona AF, Rojas L, Wills B, Bernal L, Ruiz-Patino A, Arrieta O, et al. Efficacy and safety of Levetiracetam vs. other antiepileptic drugs in Hispanic patients with glioblastoma. J Neurooncol. 2018;136: 363–371. doi: 10.1007/s11060-017-2660-0 29177594

25. Knudsen-Baas KM, Engeland A, Gilhus NE, Storstein AM, Owe JF. Does the choice of antiepileptic drug affect survival in glioblastoma patients? J Neurooncol. 2016;129: 461–469. doi: 10.1007/s11060-016-2191-0 27377653

26. Vecht CJ, Kerkhof M, Duran-Pena A. Seizure prognosis in brain tumors: new insights and evidence-based management. Oncologist. 2014;19: 751–759. doi: 10.1634/theoncologist.2014-0060 24899645

27. Kim YH, Kim T, Joo JD, Han JH, Kim YJ, Kim IA, et al. Survival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme. Cancer. 2015;121: 2926–2932. doi: 10.1002/cncr.29439 25975354

28. Oberndorfer S, Piribauer M, Marosi C, Lahrmann H, Hitzenberger P, Grisold W. P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy. J Neurooncol. 2005;72: 255–260. doi: 10.1007/s11060-004-2338-2 15937649

29. Blough MD, Zlatescu MC, Cairncross JG. O6-methylguanine-DNA methyltransferase regulation by p53 in astrocytic cells. Cancer Res. 2007;67: 580–584. doi: 10.1158/0008-5472.CAN-06-2782 17234766


Článek vyšel v časopise

PLOS One


2019 Číslo 12