Pediatric Drugs

, Volume 20, Issue 4, pp 293–301 | Cite as

The Use of Ommaya Reservoirs to Deliver Central Nervous System-Directed Chemotherapy in Childhood Acute Lymphoblastic Leukaemia

  • Ruairi Wilson
  • Caroline Osborne
  • Christina HalseyEmail author
Therapy in Practice


Prophylactic eradication of central nervous system (CNS) leukaemia is the current standard of care in treating childhood acute lymphoblastic leukaemia (ALL). This is conventionally achieved through regular lumbar punctures with intrathecal injections of methotrexate into the cerebrospinal fluid (CSF). Ommaya reservoirs are subcutaneous implantable devices that provide a secure route of drug delivery into the CSF via an intraventricular catheter. They are an important alternative in cases where intrathecal injection via lumbar puncture is difficult. Among UK Paediatric Principal Treatment Centres for ALL we found considerable variation in methotrexate dosing when using an Ommaya reservoir. We review the current safety and theoretical considerations when using Ommaya reservoirs and evidence for methotrexate dose adjustments via this route. We conclude by summarising the pragmatic consensus decision to use 50% of the conventional intrathecal dose of methotrexate when it is administered via Ommaya reservoir in front-line ALL therapy.



The authors would like to thank all the participating UK Paediatric Principal Treatment Centres for providing data on current dosing strategies and the UK Childhood Leukaemia Clinicians Network for review of the data and agreement of a consensus approach.

Compliance with Ethical Standards


There was no external funding for this work.

Conflict of interest

Ruairi Wilson, Caroline Osborne, and Christina Halsey declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.


  1. 1.
    Pui CH, Howard SC. Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol. 2008;9(3):257–68.CrossRefPubMedGoogle Scholar
  2. 2.
    Vora A, Goulden N, Wade R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013;14(3):199–209.CrossRefPubMedGoogle Scholar
  3. 3.
    Burger B, Zimmermann M, Mann G, et al. Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture. J Clin Oncol. 2003;21(2):184–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360(60):2730–41.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Halsey C, Buck G, Richards S, Vargha-Khadem F, Hill F, Gibson B. The impact of therapy for childhood acute lymphoblastic leukaemia on intelligence quotients; results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI. J Hematol Oncol. 2011;4:42.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Veerman AJ, Kamps WA, van den Berg H, et al. Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997–2004). Lancet Oncol. 2009;10(10):957–66.CrossRefPubMedGoogle Scholar
  7. 7.
    Pui CH, Sandlund JT, Pei D, et al. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children’s Research Hospital. Blood. 2004;104(9):2690–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Möricke A, Reiter A, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008;111(9):4477–89.CrossRefPubMedGoogle Scholar
  9. 9.
    Moghrabi A, Levy DE, Asselin B, et al. Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood. 2007;109(3):896–904.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ommaya AK. Subcutaneous reservoir and pump for sterile access to ventricular cerebrospinal fluid. Lancet. 1963;2(7315):983–4.CrossRefPubMedGoogle Scholar
  11. 11.
    Meijer L, Walker D, Slavc I. Intra-cerebrospinal fluid therapy for leptomeningeal metastases in medulloblastoma. In: Kombogiorgas DA, editor. The medulloblastoma book. Hauppauge: Nova Science Publishers, Inc.; 2014.Google Scholar
  12. 12.
    Peyrl A, Chocholous M, Azizi AA, Czech T, Dorfer C, Mitteregger D, Gojo J, Minichmayr E, Slavc I. Safety of Ommaya reservoirs in children with brain tumors: a 20-year experience with 5472 intraventricular drug administrations in 98 patients. J Neurooncol. 2014;120(1):139–45.CrossRefPubMedGoogle Scholar
  13. 13.
    Mead PA, Safdieh JE, Nizza P, Tuma S, Sepkowitz KA. Ommaya reservoir infections: a 16-year retrospective analysis. J Infect. 2014;68(3):225–30.CrossRefPubMedGoogle Scholar
  14. 14.
    Young GA, Milliken S, Jurd J, Poulgrain P, Vincent PC. The intraventricular reservoir in the treatment of neurological disease secondary to hematological malignancy: an eight year experience. Aust NZ J Med. 1986;16(3):373–7.CrossRefGoogle Scholar
  15. 15.
    Lishner M, Perrin RG, Feld R, Messner HA, Tuffnell PG, Elhakim T, Matlow A, Curtis JE. Complications associated with Ommaya reservoirs in patients with cancer. The Princess Margaret Hospital experience and a review of the literature. Arch Intern Med. 1990;150(1):173–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Browne MJ, Dinndorf PA, Perek D, Commers J, Bleyer WA, Poplack DG, Pizzo PA. Infectious complications of intraventricular reservoirs in cancer patients. Pediatr Infect Dis J. 1987;6(2):182–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Bleyer WA, Pizzo PA, Spence AM, Platt WD, Benjamin DR, Kolins CJ, Poplack DG. The Ommaya reservoir: newly recognized complications and recommendations for insertion and use. Cancer. 1978;41(6):2431–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Packer RJ, Zimmerman RA, Rosenstock J, et al. Focal encephalopathy following methotrexate therapy: administration via a misplaced intraventricular catheter. Arch Neurol. 1981;38:450–2.CrossRefPubMedGoogle Scholar
  19. 19.
    Colamaria V, Carabello R, Borgna-Pignatti C, et al. Transient focal leukoencephalopathy following intraventricular methotrexate and cytarabine; a complication of Ommaya reservoir: case report and review of the literature. Child’s Nerv Syst. 1990;6:231–5.CrossRefGoogle Scholar
  20. 20.
    Kennedy BC, Brown LT, Komotar RJ, McKhann GM 2nd. Frameless stereotactic ommaya reservoir placement: efficacy and complication comparison with frame-based technique. Stereotact Funct Neurosurg. 2015;93(6):415–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Weiner GM, Chivukula S, Chen CJ, Ding D, Engh JA, Amankulor N. Ommaya reservoir with ventricular catheter placement for chemotherapy with frameless and pinless electromagnetic surgical neuronavigation. Clin Neurol Neurosurg. 2015;130:61–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Morgenstern PF, Connors S, Reiner AS, Greenfield JP. Image guidance for placement of ommaya reservoirs: comparison of fluoroscopy and frameless stereotactic navigation in 145 patients. World Neurosurg. 2016;93:154–8.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Inaba H, Khan RB, Laningham FH, Crews KR, Pui CH, Daw NC. Clinical and radiological characteristics of methotrexate-induced acute encephalopathy in pediatric patients with cancer. Ann Oncol. 2008;19:178–84.CrossRefPubMedGoogle Scholar
  24. 24.
    Bhojwani D, et al. Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol. 2014;32(9):949–59.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bond J, Hough R, Moppett J, Vora A, Mitchell C, Goulden N. ‘Stroke-like syndrome’ caused by intrathecal methotrexate in patients treated during the UKALL 2003 trial. Leukaemia. 2013;27(4):1765–9.Google Scholar
  26. 26.
    Cheung YT, et al. Leukoencephalopathy and long-term neurobehavioural, neurocognitive, and brain imaging outcomes in survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy: a longitudinal analysis. Lancet Hematol. 2016;3(10):e456–66.CrossRefGoogle Scholar
  27. 27.
    Schmiegelow K, Attarbaschi A, Barzilai S, et al. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus. Lancet Oncol. 2016;17(6):e231–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Krull KR, et al. Chemotherapy pharmacodynamics and neuroimaging and neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia. J Clin Oncol. 2016;34(22):2644–53.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jacola LM, et al. Longitudinal assessment of neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia treated on a contemporary chemotherapy protocol. J Clin Oncol. 2016;34(11):1239–47.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Krull KR, Brinkman TM, Li C, Armstrong GT, Ness KK, Srivastava DK, Gurney JG, Kimberg C, Krasin MJ, Pui CH, Robinson LL, Hudson MM. Neurocognitive outcomes decades after treatment for childhood acute lymphoblastic leukaemia: a report from the St Jude lifetime cohort study. J Clin Oncol. 2013;31(35):4407–15.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kanellopoulos A, et al. Neurocognitive outcome in very long-term survivors of childhood acute lymphoblastic leukemia after treatment with chemotherapy only. Pediatr Blood Cancer. 2016;63(1):133–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Mahoney DH Jr, Shuster JJ, Nitschke R, et al. Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy—a Pediatric Oncology Group study. J Clin Oncol. 1998;16(5):1712–22.CrossRefPubMedGoogle Scholar
  33. 33.
    Forster VJ, van Delft FW, Baird SF, Mair S, Skinner R, Halsey C. Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients. Cancer Chemother Pharmacol. 2016;78(5):1093–6.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Goldie JH, Price LA, Harrap KR. Methotrexate toxicity: correlation with duration of administration, plasma levels, dose and excretion pattern. Eur J Cancer. 1972;8(4):409–14.CrossRefPubMedGoogle Scholar
  35. 35.
    Shapiro WR, Young DF, Mehta BM. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med. 1975;293(4):161–6.CrossRefPubMedGoogle Scholar
  36. 36.
    Bleyer WA, Poplack DG, Simon RM. “Concentration × time” methotrexate via a subcutaneous reservoir: a less toxic regimen for intraventricular chemotherapy of central nervous system neoplasms. Blood. 1978;51(5):835–42.PubMedGoogle Scholar
  37. 37.
    Bostrom BC, Erdmann GR, Kamen BA. Systemic methotrexate exposure is greater after intrathecal than after oral administration. J Pediatr Hematol Oncol. 2003;25(2):114–7.CrossRefPubMedGoogle Scholar
  38. 38.
    Thyss A, Suciu S, Bertrand Y, et al. Systemic effect of intrathecal methotrexate during the initial phase of treatment of childhood acute lymphoblastic leukemia. The European Organization for Research and Treatment of Cancer Children’s Leukemia Cooperative Group. J Clin Oncol. 1997;15(5):1824–30.CrossRefPubMedGoogle Scholar
  39. 39.
    Mehta BM, Glass JP, Shapiro WR. Serum and cerebrospinal fluid distribution of 5-methyltetrahydrofolate after intravenous calcium leucovorin and intra-ommaya methotrexate administration in patients with meningeal carcinomatosis. Cancer Res. 1983;43:435–8.PubMedGoogle Scholar
  40. 40.
    Ells LJ, Hancock C, Copley VR, et al. Prevalence of severe childhood obesity in England: 2006–2013. Arch Dis Child. 2015;100(7):631–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Lakshman R, Elks CE, Ong KK. Childhood obesity. Circulation. 2012;126(14):1770–9.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Steinherz P, Jereb B, Galicich J. Therapy of CNS leukemia with intraventricular chemotherapy and low-dose neuraxis radiotherapy. J Clin Oncol. 1985;3(9):1217–26.CrossRefPubMedGoogle Scholar
  43. 43.
    Bleyer WA, Poplack DG. Intraventricular versus intralumbar methotrexate for central-nervous system leukaemia: prolonged remission with the ommaya reservoir. Med Pediatr Oncol. 1979;6:2017–213.CrossRefGoogle Scholar
  44. 44.
    Iacoangeli M, Roselli R, Pagano L, et al. Intrathecal chemotherapy for treatment of overt meningeal leukaemia: comparison between intraventricular and traditional intralumbar route. Ann Oncol. 1995;6:377–82.CrossRefPubMedGoogle Scholar
  45. 45.
    Bleyer WA. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer. 1978;41(1):36–51.CrossRefPubMedGoogle Scholar
  46. 46.
    Hryniuk WM, Bertino JR. Treatment of leukemia with large doses of methotrexate and folinic acid: clinical–biochemical correlates. J Clin Invest. 1969;48(11):2140–55.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Ettinger LJ, Chervinsky DS, Freeman AI, Creaven PJ. Pharmacokinetics of methotrexate following intravenous and intraventricular administration in acute lymphocytic leukemia and non-Hodgkin’s lymphoma. Cancer. 1982;50(9):1676–82.CrossRefPubMedGoogle Scholar
  48. 48.
    Mauer AM. Cell Kinetics and practical consequences for therapy of acute leukaemia. N Engl J Med. 1975;293:389–93.CrossRefGoogle Scholar
  49. 49.
    Strother DR, Glynn-Barnhart A, Kovnar E, Gregory RE, Murphy SB. Variability in the disposition of intraventricular methotrexate: a proposal for rational dosing. J Clin Oncol. 1989;7(11):1741–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Kuo AH-M, Xenophon Y, Galicich H, Fried J, Clarkson BD. Proliferative kinetics of central nervous system (CNS) leukaemia. Cancer. 1975;36:232–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Tsuchiya J, Moteki M, Shimano S, Shinonome S, Suda T, Omine M, Maekawa T. Proliferative kinetics of the leukaemic cells in meningeal leukaemia. Cancer. 1978;42:1255–62.CrossRefPubMedGoogle Scholar
  52. 52.
    Brinker T, Stopa E, Morrison J, Klinge P. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS. 2014;11:10.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Bleyer WA, Drake JC, Chabner BA. Neurotoxicity and elevated cerebrospinal-fluid methotrexate concentration in meningeal leukemia. N Engl J Med. 1973;289(15):770–3.CrossRefPubMedGoogle Scholar
  54. 54.
    Morse M, Savitch J, Balis F, Miser J, Feusner J, Reaman G, Poplack D, Bleyer A. Altered central nervous system pharmacology of methotrexate in childhood leukemia: another sign of meningeal relapse. J Clin Oncol. 1985;3(1):19–24.CrossRefPubMedGoogle Scholar
  55. 55.
    Grossman SA, Trump DL, Chen DC, Thompson G, Camargo EE. Cerebrospinal fluid flow abnormalities in patients with neoplastic meningitis. An evaluation using 111indium-DTPA ventriculography. Am J Med. 1982;73(5):641–7.CrossRefPubMedGoogle Scholar
  56. 56.
    Chiro GD, Hammock MK, Bleyer WA. Spinal descent of cerebrospinal fluid in man. Neurology. 1976;26(1):1–8.CrossRefPubMedGoogle Scholar
  57. 57.
    Larson S, Schall G, Di Chrio G. The influence of previous lumbar puncture and pneumoencephalography on the incidence of unsuccessful radioisotope cisternography. J Nucl Med. 1971;12:555–7.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life SciencesUniversity of GlasgowGlasgowUK
  2. 2.Pharmacy DepartmentAlder Hey Children’s NHS Foundation TrustLiverpoolUK
  3. 3.Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life SciencesUniversity of GlasgowGlasgowUK

Personalised recommendations