Skip to main content
SpringerLink
Log in

Valproic acid was well tolerated in heavily pretreated pediatric patients with high-grade glioma

  • Clinical Study - Patient Study
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Valproic acid (VPA) inhibits histone deacetylase and has been reported to induce apoptosis in glioma. We report 44 heavily pretreated pediatric patients with high-grade glioma or diffuse intrinsic pontine glioma who received VPA as oral continues maintenance treatment with individual dose adaptation. The tumor status when starting the drug was: no measurable disease in 12, measurable but stable disease in 12, and measurable progressive disease in 22 patients. Average trough blood levels of VPA were 99 mg/l. The most frequent complaint was somnolence (three patients), but no severe toxicity was reported. One relapse patient responded, early progression of disease was observed in three frontline patients and in six relapsed patients. Median overall survival duration for all patients was 1.33 years, with large differences between first-line (5-year overall survival, 44%) and relapse therapy (5-year overall survival, 14%). This shows that valproate is safe in this patient population. The moderate tumor efficacy encourages studying the drug further as an element of multi-agent protocols.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Lance JW, Anthony M (1975) Sodium valproate in the management of intractable epilepsy: comparison with clonazepam. Proc Aust Assoc Neurol 12:55–60

    PubMed  CAS  Google Scholar 

  2. Post RM, Uhde TW (1983) Treatment of mood disorders with antiepileptic medications: clinical and theoretical implications. Epilepsia 24(Suppl 2):S97–S108. doi:10.1111/j.1528-1157.1983.tb04652.x

    Article  PubMed  Google Scholar 

  3. Anthony M, Hinterberger H, Lance JW (1977) Plasma sodium valproate levels and clinical response in epilepsy. Clin Exp Neurol 14:208–215

    PubMed  CAS  Google Scholar 

  4. Limdi NA, Knowlton RK, Cofield SS, Ver Hoef LW, Paige AL, Dutta S et al (2007) Safety of rapid intravenous loading of valproate. Epilepsia 48:478–483. doi:10.1111/j.1528-1167.2007.00989.x

    Article  PubMed  CAS  Google Scholar 

  5. Brown NA, Kao J, Fabro S (1980) Teratogenic potential of valproic acid. Lancet 1:660–661. doi:10.1016/S0140-6736(80)91159-9

    Article  PubMed  CAS  Google Scholar 

  6. Isojarvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla VV (1993) Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 329:1383–1388. doi:10.1056/NEJM199311043291904

    Article  PubMed  CAS  Google Scholar 

  7. Regan CM (1985) Therapeutic levels of sodium valproate inhibit mitotic indices in cells of neural origin. Brain Res 347:394–398. doi:10.1016/0006-8993(85)90207-0

    Article  PubMed  CAS  Google Scholar 

  8. Selby R, Nisbet-Brown E, Basran RK, Chang L, Olivieri NF (1997) Valproic acid and augmentation of fetal hemoglobin in individuals with and without sickle cell disease. Blood 90:891–893

    PubMed  CAS  Google Scholar 

  9. Kieslich M, Schwabe D, Cinatl J Jr, Driever PH (2003) Increase of fetal hemoglobin synthesis indicating differentiation induction in children receiving valproic acid. Pediatr Hematol Oncol 20:15–22. doi:10.1080/713842215

    Article  PubMed  CAS  Google Scholar 

  10. Knupfer MM, Hernaiz-Driever P, Poppenborg H, Wolff JE, Cinatl J (1998) Valproic acid inhibits proliferation and changes expression of CD44 and CD56 of malignant glioma cells in vitro. Anticancer Res 18:3585–3589

    PubMed  CAS  Google Scholar 

  11. Driever PH, Knupfer MM, Cinatl J, Wolff JE (1999) Valproic acid for the treatment of pediatric malignant glioma. Klin Padiatr 211:323–328

    PubMed  CAS  Google Scholar 

  12. Witt O, Schweigerer L, Driever PH, Wolff J, Pekrun A (2004) Valproic acid treatment of glioblastoma multiforme in a child. Pediatr Blood Cancer 43:181. doi:10.1002/pbc.20083

    Article  PubMed  Google Scholar 

  13. Driever PH, Wagner S, Hofstadter F, Wolff JE (2004) Valproic acid induces differentiation of a supratentorial primitive neuroectodermal tumor. Pediatr Hematol Oncol 21:743–751. doi:10.1080/08880010490514985

    Article  PubMed  Google Scholar 

  14. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276:36734–36741. doi:10.1074/jbc.M101287200

    Article  PubMed  CAS  Google Scholar 

  15. Das CM, Aguilera D, Vasquez H, Prasad P, Zhang M, Wolff JE et al (2007) Valproic acid induces p21 and topoisomerase-II (alpha/beta) expression and synergistically enhances etoposide cytotoxicity in human glioblastoma cell lines. J Neurooncol 85:159–170. doi:10.1007/s11060-007-9402-7

    Article  PubMed  CAS  Google Scholar 

  16. Blaheta RA, Michaelis M, Driever PH, Cinatl J Jr (2005) Evolving anticancer drug valproic acid: insights into the mechanism and clinical studies. Med Res Rev 25:383–397. doi:10.1002/med.20027

    Article  PubMed  CAS  Google Scholar 

  17. Dong G, Wang L, Wang CY, Yang T, Kumar MV, Dong Z (2008) Induction of apoptosis in renal tubular cells by histone deacetylase inhibitors, a family of anticancer agents. J Pharmacol Exp Ther 325:978–984. doi:10.1124/jpet.108.137398

    Article  PubMed  CAS  Google Scholar 

  18. Johnson J, Pahuja A, Graham M, Hering B, Hancock WW, Bansal-Pakala P (2008) Effects of histone deacetylase inhibitor SAHA on effector and FOXP3+ regulatory T cells in rhesus macaques. Transplant Proc 40:459–461. doi:10.1016/j.transproceed.2008.01.039

    Article  PubMed  CAS  Google Scholar 

  19. Huang L, Sowa Y, Sakai T, Pardee AB (2000) Activation of the p21WAF1/CIP1 promoter independent of p53 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) through the Sp1 sites. Oncogene 19:5712–5719. doi:10.1038/sj.onc.1203963

    Article  PubMed  CAS  Google Scholar 

  20. Yi X, Wei W, Wang SY, Du ZY, Xu YJ, Yu XD (2008) Histone deacetylase inhibitor SAHA induces ERalpha degradation in breast cancer MCF-7 cells by CHIP-mediated ubiquitin pathway and inhibits survival signaling. Biochem Pharmacol 75:1697–1705. doi:10.1016/j.bcp. 2007.10.035

    Article  PubMed  CAS  Google Scholar 

  21. Domingo-Domènech J, Pippa R, Tápia M, Gascón P, Bachs O, Bosch M (2008) Inactivation of NF-kappaB by proteasome inhibition contributes to increased apoptosis induced by histone deacetylase inhibitors in human breast cancer cells. Breast Cancer Res Treat (in press)

  22. Carlisi D, Vassallo B, Lauricella M, Emanuele S, D’Anneo A, Di Leonardo E et al (2008) Histone deacetylase inhibitors induce in human hepatoma HepG2 cells acetylation of p53 and histones in correlation with apoptotic effects. Int J Oncol 32:177–184

    PubMed  CAS  Google Scholar 

  23. Hassig CA, Symons KT, Guo X, Nguyen PM, Annable T, Wash PL et al (2008) KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther 7:1054–1065. doi:10.1158/1535-7163.MCT-07-2347

    Article  PubMed  CAS  Google Scholar 

  24. Fournel M, Bonfils C, Hou Y, Yan PT, Trachy-Bourget MC, Kalita A et al (2008) MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther 7:759–768. doi:10.1158/1535-7163.MCT-07-2026

    Article  PubMed  CAS  Google Scholar 

  25. Petrella A, D’Acunto CW, Rodriquez M, Festa M, Tosco A, Bruno I et al (2008) Effects of FR235222, a novel HDAC inhibitor, in proliferation and apoptosis of human leukaemia cell lines: role of annexin A1. Eur J Cancer 44:740–749. doi:10.1016/j.ejca.2008.01.023

    Article  PubMed  CAS  Google Scholar 

  26. Spiller SE, Ditzler SH, Pullar BJ, Olson JM (2008) Response of preclinical medulloblastoma models to combination therapy with 13-cis retinoic acid and suberoylanilide hydroxamic acid (SAHA). J Neurooncol 87:133–141. doi:10.1007/s11060-007-9505-1

    Article  PubMed  CAS  Google Scholar 

  27. Blumenschein GR Jr, Kies MS, Papadimitrakopoulou VA, Lu C, Kumar AJ, Ricker JL et al (2008) Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Invest New Drugs 26:81–87. doi:10.1007/s10637-007-9075-2

    Article  PubMed  CAS  Google Scholar 

  28. Atmaca A, Al-Batran SE, Maurer A, Neumann A, Heinzel T, Hentsch B et al (2007) Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial. Br J Cancer 97:177–182. doi:10.1038/sj.bjc.6603851

    Article  PubMed  CAS  Google Scholar 

  29. Wolff JE, Boos J, Kuhl J (1996) HIT-GBM: multicenter study of treatment of children with malignant glioma. Klin Padiatr 208:193–196

    PubMed  CAS  Google Scholar 

  30. Bouffet E, Khelfaoui F, Philip I, Biron P, Brunat-Mentigny M, Philip T (1997) High-dose carmustine for high-grade gliomas in childhood. Cancer Chemother Pharmacol 39:376–379. doi:10.1007/s002800050586

    Article  PubMed  CAS  Google Scholar 

  31. Estlin EJ, Lashford L, Ablett S, Price L, Gowing R, Gholkar A et al (1998) Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children’s Cancer Study Group. Br J Cancer 78:652–661

    PubMed  CAS  Google Scholar 

  32. Liu L, Vapiwala N, Munoz LK, Winick NJ, Weitman S, Strauss LC et al (2001) A phase I study of cranial radiation therapy with concomitant continuous infusion paclitaxel in children with brain tumors. Med Pediatr Oncol 37:390–392. doi:10.1002/mpo.1215

    Article  PubMed  CAS  Google Scholar 

  33. Broniscer A, Gajjar A (2004) Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist. Oncologist 9:197–206. doi:10.1634/theoncologist.9-2-197

    Article  PubMed  Google Scholar 

  34. Donaldson SS, Laningham F, Fisher PG (2006) Advances toward an understanding of brainstem gliomas. J Clin Oncol 24:1266–1272. doi:10.1200/JCO.2005.04.6599

    Article  PubMed  CAS  Google Scholar 

  35. Sposto R, Ertel IJ, Jenkin RD, Boesel CP, Venes JL, Ortega JA et al (1989) The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the Childrens Cancer Study Group. J Neurooncol 7:165–177. doi:10.1007/BF00165101

    Article  PubMed  CAS  Google Scholar 

  36. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi:10.1056/NEJMoa043330

    Article  PubMed  CAS  Google Scholar 

  37. Wolff JE, Boos J, Krahling KH, Jurgens H (1996) Second temporal remission in a malignant glioma with trofosfamide and etoposide: a case report. Klin Padiatr 208:190–192

    Article  PubMed  CAS  Google Scholar 

  38. Wolff JE, Molenkamp G, Westphal S, Pietsch T, Gnekow A, Kortmann RD et al (2000) Oral trofosfamide and etoposide in pediatric patients with glioblastoma multiforme. Cancer 89:2131–2137. doi :10.1002/1097-0142(20001115)89:10<2131::AID-CNCR14>3.0.CO;2-J

    Article  PubMed  CAS  Google Scholar 

  39. Wolff JE, Westphal S, Molenkamp G, Gnekow A, Warmuth-Metz M, Rating D et al (2002) Treatment of paediatric pontine glioma with oral trophosphamide and etoposide. Br J Cancer 87:945–949. doi:10.1038/sj.bjc.6600552

    Article  PubMed  CAS  Google Scholar 

  40. Wolff JE, Wagner S, Sindichakis M, Pietsch T, Gnekow A, Kortmann RD et al (2002) Simultaneous radiochemotherapy in pediatric patients with high-grade glioma: a phase I study. Anticancer Res 22:3569–3572

    PubMed  Google Scholar 

  41. Wolff JE, Wagner S, Reinert C, Gnekow A, Kortmann RD, Kuhl J et al (2006) Maintenance treatment with interferon-gamma and low-dose cyclophosphamide for pediatric high-grade glioma. J Neurooncol 79:315–321. doi:10.1007/s11060-006-9147-8

    Article  PubMed  CAS  Google Scholar 

  42. Wolff JE, Classen CF, Wagner S, Kortmann RD, Palla SL, Pietsch T, Kühl J, Gnekow A, Kramm CM (2008) Subpopulations of malignant gliomas in pediatric patients: analysis of the HIT-GBM database. J Neurooncol 87(2):155–164

    Article  Google Scholar 

  43. Kramm CM, Wagner S, Van Gool S, Schmid H, Strater R, Gnekow A et al (2006) Improved survival after gross total resection of malignant gliomas in pediatric patients from the HIT-GBM studies. Anticancer Res 26:3773–3779

    PubMed  Google Scholar 

  44. Benesch M, Wagner S, Berthold F, Wolff JE (2005) Primary dissemination of high-grade gliomas in children: experiences from four studies of the Pediatric Oncology and Hematology Society of the German Language Group (GPOH). J Neurooncol 72:179–183. doi:10.1007/s11060-004-3546-5

    Article  PubMed  Google Scholar 

  45. Spiller HA, Krenzelok EP, Klein-Schwartz W, Winter ML, Weber JA, Sollee DR et al (2000) Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. J Toxicol 38:755–760

    CAS  Google Scholar 

  46. Koenig SA, Buesing D, Longin E, Oehring R, Haussermann P, Kluger G et al (2006) Valproic acid-induced hepatopathy: nine new fatalities in Germany from 1994 to 2003. Epilepsia 47:2027–2031. doi:10.1111/j.1528-1167.2006.00846.x

    Article  PubMed  CAS  Google Scholar 

  47. Bohan TP, Helton E, McDonald I, Konig S, Gazitt S, Sugimoto T et al (2001) Effect of L-carnitine treatment for valproate-induced hepatotoxicity. Neurology 56:1405–1409

    PubMed  CAS  Google Scholar 

  48. Wagner S, Warmuth-Metz M, Emser A, Gnekow AK, Strater R, Rutkowski S et al (2006) Treatment options in childhood pontine gliomas. J Neurooncol 79:281–287. doi:10.1007/s11060-006-9133-1

    Article  PubMed  Google Scholar 

  49. Camphausen K, Cerna D, Scott T, Sproull M, Burgan WE, Cerra MA et al (2005) Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid. Int J Cancer 114:380–386. doi:10.1002/ijc.20774

    Article  PubMed  CAS  Google Scholar 

  50. Zaskodova D, Rezacova M, Vavrova J, Vokurkova D, Tichy A (2006) Effect of valproic acid, a histone deacetylase inhibitor, on cell death and molecular changes caused by low-dose irradiation. Ann N Y Acad Sci 1091:385–398. doi:10.1196/annals.1378.082

    Article  PubMed  CAS  Google Scholar 

  51. Marchion DC, Bicaku E, Daud AI, Sullivan DM, Munster PN (2005) In vivo synergy between topoisomerase II and histone deacetylase inhibitors: predictive correlates. Mol Cancer Ther 4:1993–2000. doi:10.1158/1535-7163.MCT-05-0194

    Article  PubMed  CAS  Google Scholar 

  52. Masoudi A, Elopre M, Amini E, Nagel ME, Ater JL, Gopalakrishnan V, Wolff JEA (2008) Influence of Valproic acid on outcome of high-grade gliomas in children. AntiCancer Res (accepted)

  53. Wagner S, Reinert C, Schmid HJ, Liebeskind AK, Jorch N, Langler A et al (2005) High-dose methotrexate prior to simultaneous radiochemotherapy in children with malignant high-grade gliomas. Anticancer Res 25:2583–2587

    PubMed  CAS  Google Scholar 

  54. Wagner S, Csatary CM, Gosztonyi G, Koch HC, Hartmann C, Peters O et al (2006) Combined treatment of pediatric high-grade glioma with the oncolytic viral strain MTH-68/H and oral valproic acid. APMIS 114:731–743. doi:10.1111/j.1600-0463.2006.apm_516.x

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

Supported by Deutsche Kinderkrebsstiftung, Germany and Core Grant CA 16672. The original HIT-GBM® Database has been used before as a source for analyses with different focuses and different subsets of data [39, 42–44, 53, 54]. This analysis only uses the data generated prospectively for including patients formally enrolled on the treatment study and the registry or at least the registry until 2003 with follow up updated in 2006. The other HIT-GBM publications have been based on overlapping but not identical patient populations.

Author information

Authors and Affiliations

  1. Children’s Cancer Hospital, Department of Pediatrics, Unit 87, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, USA

    Johannes E. A. Wolff

  2. Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Johannes E. A. Wolff

  3. Pediatric Hematology and Oncology, University of Regensburg, Klinik St. Hedwig, Regensburg, Germany

    Johannes E. A. Wolff

  4. Department of Pediatric Oncology, Martin-Luther University Halle-Wittenberg, Halle, Germany

    Christof Kramm

  5. Department of Radiation Oncology, University of Leipzig, Leipzig, Germany

    Rolf-Dieter Kortmann

  6. Department of Neuropathology, University of Bonn, Bonn, Germany

    Torsten Pietsch

  7. Children’s University Hospital, University of Wuerzburg, Wuerzburg, Germany

    Stefan Rutkowski

  8. Department of Pediatrics, Krankenanstalten Gilead, Bielefeld, Germany

    Norbert Jorch

  9. Department of Pediatrics, Klinik für Kinder und Jugendliche, Augsburg, Germany

    Astrid Gnekow

  10. Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Pablo Hernáiz Driever

Authors
  1. Johannes E. A. Wolff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christof Kramm
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rolf-Dieter Kortmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Torsten Pietsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stefan Rutkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Norbert Jorch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Astrid Gnekow
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pablo Hernáiz Driever
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Johannes E. A. Wolff.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wolff, J.E.A., Kramm, C., Kortmann, RD. et al. Valproic acid was well tolerated in heavily pretreated pediatric patients with high-grade glioma. J Neurooncol 90, 309–314 (2008). https://doi.org/10.1007/s11060-008-9662-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-008-9662-x

Keywords

Search

Navigation