Journal of Neuro-Oncology

, Volume 128, Issue 3, pp 463–471 | Cite as

Intraventricular etoposide safety and toxicity profile in children and young adults with refractory or recurrent malignant brain tumors

  • Kristian W. PajtlerEmail author
  • Stephan Tippelt
  • Nele Siegler
  • Stefanie Reichling
  • Martina Zimmermann
  • Ruth Mikasch
  • Udo Bode
  • Astrid Gnekow
  • Torsten Pietsch
  • Martin Benesch
  • Stefan Rutkowski
  • Gudrun Fleischhack
Clinical Study


Systemic administration of etoposide is effective in treating metastatic, recurrent or refractory brain tumors, but penetration into the cerebrospinal fluid is extremely poor. This study was designed to determine the safety and toxicity profile of intraventricular etoposide administration and was affiliated with the prospective, multicenter, nonblinded, nonrandomized, multi-armed HIT-REZ-97 trial. The study enrolled 68 patients, aged 1.1–34.6 (median age 11 years). Adverse events that could possibly be related to intraventricular etoposide therapy were documented and analyzed. Intraventricular etoposide was simultaneously administered with either oral or intravenous chemotherapy in 426 courses according to three major schedules varying in dosing (0.25–1 mg), frequency of administration (bolus injection, every 12 or 24 h), course duration (5–10 days) and length of interval between courses (2–5 weeks). Potential treatment-related adverse effects included transient headache, seizures, infection of the reservoir, nausea and neuropsychological symptoms. Hematological side effects were not observed. One patient, with history of multiple prior therapies, who received long-term intraventricular and oral etoposide treatment developed acute myeloid leukemia as a secondary malignancy. Overall intraventricular etoposide is well tolerated. The results of this study have warranted a phase II trial to determine the effectiveness of this regimen in disease stages with very limited therapeutic options.


Ependymoma Medulloblastoma ATRT Relapse Progression Pediatric brain tumors 



We thank our patients and their families for participation and contribution. We are also grateful to our colleagues and data managers of the participating hospitals for their valuable cooperation. This study was supported by research grants from the German Children Cancer Foundation DKS 99.02/DKS 2002.0.4 and grants to the Reference Centers for Neuroradiology and Neuropathology of the HIT network from the German Children Cancer Foundation. The authors thank K. Astrahantseff for manuscript editing.

Supplementary material

11060_2016_2133_MOESM1_ESM.pdf (98 kb)
Flow chart of the HIT-REZ-97 trial comprising a high-dose, a chemotherapy and a documentation arm. Localized radiotherapy and/or tumor resection were used in all treatment arms.
11060_2016_2133_MOESM2_ESM.pdf (192 kb)
Supplementary material 2 (PDF 191 kb)


  1. 1.
    Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, Wolinsky Y, Kruchko C, Barnholtz-Sloan J (2014) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro Oncol 16(Suppl 4):iv1–iv63. doi: 10.1093/neuonc/nou223 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Agaoglu FY, Ayan I, Dizdar Y, Kebudi R, Gorgun O, Darendeliler E (2005) Ependymal tumors in childhood. Pediatr Blood Cancer 45:298–303CrossRefPubMedGoogle Scholar
  3. 3.
    von Hoff K, Hinkes B, Gerber NU, Deinlein F, Mittler U, Urban C, Benesch M, Warmuth-Metz M, Soerensen N, Zwiener I, Goette H, Schlegel PG, Pietsch T, Kortmann RD, Kuehl J, Rutkowski S (2009) Long-term outcome and clinical prognostic factors in children with medulloblastoma treated in the prospective randomised multicentre trial HIT’91. Eur J Cancer 45:1209–1217. doi: 10.1016/j.ejca.2009.01.015 CrossRefGoogle Scholar
  4. 4.
    Wetmore C, Herington D, Lin T, Onar-Thomas A, Gajjar A, Merchant TE (2014) Reirradiation of recurrent medulloblastoma: does clinical benefit outweigh risk for toxicity? Cancer 120:3731–3737. doi: 10.1002/cncr.28907 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Baumann GS, Wara WM, Larson DA, Sneed PK, Gutin PH, Ciricillo SF, McDermott MW, Park E, Stalpers LJ, Verhey LJ, Smith V, Petti PL, Edwards MS (1996) Gamma knife radiosurgery in children. Pediatr Neurosurg 24:193–201CrossRefPubMedGoogle Scholar
  6. 6.
    Blaney SM, Berg SL, Boddy AV (2004) Drug delivery. In: Walker DA, Perilongo G, Punt JAG, Taylor RE (eds) Brain and spinal tumors of childhood. Arnold, London, pp 228–242CrossRefGoogle Scholar
  7. 7.
    Fleischhack G, Jaehde U, Bode U (2005) Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis. Clin Pharmacokinet 44:1–31. doi: 10.2165/00003088-200544010-00001 CrossRefPubMedGoogle Scholar
  8. 8.
    Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff JE, Kortmann RD, Kuehl J (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352:978–986. doi: 10.1056/NEJMoa042176 CrossRefPubMedGoogle Scholar
  9. 9.
    Fisher PG, Kadan-Lottick NS, Korones DN (2002) Intrathecal thiotepa: reappraisal of an established therapy. J Pediatr Hematol Oncol 24:274–278CrossRefPubMedGoogle Scholar
  10. 10.
    Lassaletta A, Perez-Olleros P, Scaglione C, Sirvent S, De Prada I, Perez-Martinez A, Ruiz-Hernandez A, Madero L (2007) Successful treatment of intracranial ependymoma with leptomeningeal spread with systemic chemotherapy and intrathecal liposomal cytarabine in a two-year-old child. J Neuro Oncol 83:303–306. doi: 10.1007/s11060-006-9327-6 CrossRefGoogle Scholar
  11. 11.
    Bomgaars L, Geyer JR, Franklin J, Dahl G, Park J, Winick NJ, Klenke R, Berg SL, Blaney SM (2004) Phase I trial of intrathecal liposomal cytarabine in children with neoplastic meningitis. J Clin Oncol 22:3916–3921. doi: 10.1200/JCO.2004.01.046 CrossRefPubMedGoogle Scholar
  12. 12.
    von Bueren AO, von Hoff K, Pietsch T, Gerber NU, Warmuth-Metz M, Deinlein F, Zwiener I, Faldum A, Fleischhack G, Benesch M, Krauss J, Kuehl J, Kortmann RD, Rutkowski S (2011) Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology. Neuro Oncol 13:669–679. doi: 10.1093/neuonc/nor025 CrossRefGoogle Scholar
  13. 13.
    Pompe RS, von Bueren AO, Mynarek M, von Hoff K, Friedrich C, Kwiecien R, Treulieb W, Lindow C, Deinlein F, Fleischhack G, Kuehl J, Rutkowski S (2015) Intraventricular methotrexate as part of primary therapy for children with infant and/or metastatic medulloblastoma: feasibility, acute toxicity and evidence for efficacy. Eur J Cancer 51:2634–2642. doi: 10.1016/j.ejca.2015.08.009 CrossRefPubMedGoogle Scholar
  14. 14.
    Rubinstein LJ, Herman MM, Long TF, Wilbur JR (1975) Disseminated necrotizing leukoencephalopathy: a complication of treated central nervous system leukemia and lymphoma. Cancer 35:291–305CrossRefPubMedGoogle Scholar
  15. 15.
    Peyrl A, Sauermann R, Chocholous M, Azizi AA, Jager W, Hoferl M, Slavc I (2014) Pharmacokinetics and toxicity of intrathecal liposomal cytarabine in children and adolescents following age-adapted dosing. Clin Pharmacokinet 53:165–173. doi: 10.1007/s40262-013-0106-1 CrossRefPubMedGoogle Scholar
  16. 16.
    Lassaletta A, Lopez-Ibor B, Mateos E, Gonzalez-Vicent M, Perez-Martinez A, Sevilla J, Diaz MA, Madero L (2009) Intrathecal liposomal cytarabine in children under 4 years with malignant brain tumors. J Neuro Oncol 95:65–69. doi: 10.1007/s11060-009-9892-6 CrossRefGoogle Scholar
  17. 17.
    Benesch M, Siegler N, Hoff K, Lassay L, Kropshofer G, Muller H, Sommer C, Rutkowski S, Fleischhack G, Urban C (2009) Safety and toxicity of intrathecal liposomal cytarabine (Depocyte) in children and adolescents with recurrent or refractory brain tumors: a multi-institutional retrospective study. Anticancer Drugs 20:794–799. doi: 10.1097/CAD.0b013e32832f4abe CrossRefPubMedGoogle Scholar
  18. 18.
    Chamberlain MC, Kormanik PA (1997) Chronic oral VP-16 for recurrent medulloblastoma. Pediatr Neurol 17:230–234CrossRefPubMedGoogle Scholar
  19. 19.
    Ashley DM, Meier L, Kerby T, Zalduondo FM, Friedman HS, Gajjar A, Kun L, Duffner PK, Smith S, Longee D (1996) Response of recurrent medulloblastoma to low-dose oral etoposide. J Clin Oncol 14:1922–1927PubMedGoogle Scholar
  20. 20.
    Fleischhack G, Reif S, Hasan C, Jaehde U, Hettmer S, Bode U (2001) Feasibility of intraventricular administration of etoposide in patients with metastatic brain tumours. Br J Cancer 84:1453–1459. doi: 10.1054/bjoc.2001.1841 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Chang CH, Housepian EM, Herbert C Jr (1969) An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 93:1351–1359CrossRefPubMedGoogle Scholar
  22. 22.
    Sirisangtragul C, Henke G, Fleischhack G, Reif S, Kloft C, Bode U, Jaehde U (2003) Cerebrospinal fluid pharmacokinetics after different dosage regimens of intraventricular etoposide. Int J Clin Pharmacol Ther 41:606–607CrossRefPubMedGoogle Scholar
  23. 23.
    Kleihues P, Burger PC, Scheithauer BW (1993) The new WHO classification of brain tumours. Brain Pathol 3:255–268CrossRefPubMedGoogle Scholar
  24. 24.
    Kleihues P, Sobin LH (2000) World Health Organization classification of tumors. Cancer 88:2887CrossRefPubMedGoogle Scholar
  25. 25.
    Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280PubMedGoogle Scholar
  26. 26.
    NCI (2009) Common terminology criteria for adverse events v4.0. NCI, NIH, DHHS, BethesdaGoogle Scholar
  27. 27.
    WHO (1979) WHO handbook for reporting results of cancer treatment. WHO, GenevaGoogle Scholar
  28. 28.
    Slavc I, Schuller E, Falger J, Gunes M, Pillwein K, Czech T, Dietrich W, Rossler K, Dieckmann K, Prayer D, Hainfellner J (2003) Feasibility of long-term intraventricular therapy with mafosfamide (n = 26) and etoposide (n = 11): experience in 26 children with disseminated malignant brain tumors. J Neuro Oncol 64:239–247CrossRefGoogle Scholar
  29. 29.
    van der Gaast A, Sonneveld P, Mans DR, Splinter TA (1992) Intrathecal administration of etoposide in the treatment of malignant meningitis: feasibility and pharmacokinetic data. Cancer Chemother Pharmacol 29:335–337CrossRefPubMedGoogle Scholar
  30. 30.
    Pels H, Schmidt-Wolf IG, Glasmacher A, Schulz H, Engert A, Diehl V, Zellner A, Schackert G, Reichmann H, Kroschinsky F, Vogt-Schaden M, Egerer G, Bode U, Schaller C, Deckert M, Fimmers R, Helmstaedter C, Atasoy A, Klockgether T, Schlegel U (2003) Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 21:4489–4495. doi: 10.1200/JCO.2003.04.056 CrossRefPubMedGoogle Scholar
  31. 31.
    Chamberlain MC, Tsao-Wei DD, Groshen S (2006) Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis. Cancer 106:2021–2027. doi: 10.1002/cncr.21828 CrossRefPubMedGoogle Scholar
  32. 32.
    Glantz MJ, LaFollette S, Jaeckle KA, Shapiro W, Swinnen L, Rozental JR, Phuphanich S, Rogers LR, Gutheil JC, Batchelor T, Lyter D, Chamberlain M, Maria BL, Schiffer C, Bashir R, Thomas D, Cowens W, Howell SB (1999) Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 17:3110–3116PubMedGoogle Scholar
  33. 33.
    Puget S, Boddaert N, Viguier D, Kieffer V, Bulteau C, Garnett M, Callu D, Sainte-Rose C, Kalifa C, Dellatolas G, Grill J (2009) Injuries to inferior vermis and dentate nuclei predict poor neurological and neuropsychological outcome in children with malignant posterior fossa tumors. Cancer 115:1338–1347. doi: 10.1002/cncr.24150 CrossRefPubMedGoogle Scholar
  34. 34.
    Duffner PK (2010) Risk factors for cognitive decline in children treated for brain tumors. Eur J Paediatr Neurol 14:106–115. doi: 10.1016/j.ejpn.2009.10.005 CrossRefPubMedGoogle Scholar
  35. 35.
    Frange P, Alapetite C, Gaboriaud G, Bours D, Zucker JM, Zerah M, Brisse H, Chevignard M, Mosseri V, Bouffet E, Doz F (2009) From childhood to adulthood: long-term outcome of medulloblastoma patients. The Institut Curie experience (1980–2000). J Neuro Oncol 95:271–279. doi: 10.1007/s11060-009-9927-z CrossRefGoogle Scholar
  36. 36.
    Friedman DL, Whitton J, Leisenring W, Mertens AC, Hammond S, Stovall M, Donaldson SS, Meadows AT, Robison LL, Neglia JP (2010) Subsequent neoplasms in 5-year survivors of childhood cancer: the childhood cancer survivor study. J Natl Cancer Inst 102:1083–1095. doi: 10.1093/jnci/djq238 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Cowell IG, Austin CA (2012) Mechanism of generation of therapy related leukemia in response to anti-topoisomerase II agents. Intern J Environ Res Public Health 9:2075–2091. doi: 10.3390/ijerph9062075 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Kristian W. Pajtler
    • 1
    • 2
    Email author
  • Stephan Tippelt
    • 3
  • Nele Siegler
    • 3
  • Stefanie Reichling
    • 4
  • Martina Zimmermann
    • 4
  • Ruth Mikasch
    • 3
  • Udo Bode
    • 4
  • Astrid Gnekow
    • 5
  • Torsten Pietsch
    • 6
  • Martin Benesch
    • 7
  • Stefan Rutkowski
    • 8
  • Gudrun Fleischhack
    • 3
  1. 1.Division of Pediatric NeurooncologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  2. 2.Department of Pediatric Oncology, Hematology and ImmunologyUniversity Hospital HeidelbergHeidelbergGermany
  3. 3.Department of Pediatric Oncology and Hematology, Pediatrics IIIUniversity Hospital EssenEssenGermany
  4. 4.Department of Pediatric Hematology and OncologyUniversity of BonnBonnGermany
  5. 5.Hospital for Children and AdolescentsKlinikum AugsburgAugsburgGermany
  6. 6.Institute of NeuropathologyUniversity of BonnBonnGermany
  7. 7.Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent MedicineMedical University of GrazGrazAustria
  8. 8.Department of Pediatric Hematology and OncologyUniversity Medical Center Hamburg-EppendorfHamburgGermany

Personalised recommendations