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Pharmacokinetics Following Intraventricular Administration of Chemotherapy in Patients with Neoplastic Meningitis

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Intraventricular administration of chemotherapy is one approach to overcoming the limited distribution of anticancer drugs and their active metabolites into the CNS. This form of regional chemotherapy has led to effective treatment of occult and overt meningeal leukaemia in humans. In contrast, the efficacy of this therapy is extremely limited in the treatment of leptomeningeal dissemination of various solid tumours. Pharmacokinetic studies of the commonly intraventricularly applied anticancer agents in humans have demonstrated that, using low drug doses, very high drug concentrations can be achieved in the cerebrospinal fluid (CSF) and relatively high concentrations in the leptomeninges but not in the brain tissue and the plasma. Therefore, this approach is not an effective treatment for bulky disease of brain tissue, and results in minimal systemic toxicity. In comparison with intralumbar administration, lower interpatient variability of CSF drug concentrations and improved clinical efficacy were observed. ‘Concentration × time’ schedules, i.e. frequent small drug doses over a short period, enable long-term CSF exposure to cytotoxic drug concentrations while avoiding excessively high and potentially neurotoxic drug concentrations. The technique of ventriculolumbar cerebrospinal perfusion delivers continuously high drug concentrations throughout the CSF for several hours, but its widespread use is limited by the technical complexities of this approach.

In this article, the dosages, schedules and pharmacokinetic data of routinely used intraventricular agents in humans, e.g. methotrexate, cytarabine, glucocorticoids and thiotepa, are outlined in detail. In addition, pharmacokinetic data of investigational agents for intraventricular administration (diaziquone, DTC 101, mercaptopurine, mafosfamide, etoposide, topotecan, nimustine [ACNU] and bleomycin) are presented. Better understanding of the CSF pharmacology of these drugs is an essential prerequisite for safe, effective administration of these drugs. Investigational efforts are underway to verify the feasibility and efficacy of different dosages, schedules and combination therapies of these new intra-CSF agents. Current and future clinical research should also focus on methods allowing the delivery of tumoricidal drug concentrations for extended periods into the CSF and the brain tissue while minimising neurotoxicity and systemic toxicity (e.g. liposomal drug preparations, monoclonal antibodies, immunotoxins and gene therapy).

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  1. 1.

    Mahaley MS, Mettlin C, Natarajan N, et al. Analysis of patterns of care of brain tumor patients in the United States: a study of the Brain Tumor Section of the AANS and the CNS and the Commission on Cancer of the ACS. Clin Neurosurg 1990; 36: 347–52

  2. 2.

    Posner JB. Brain tumors. CA Cancer J Clin 1993 Sep-Oct; 43(5): 261–2

  3. 3.

    Nugent J, Bunn PJ, Matthews M, et al. CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer 1979; 44: 1885–93

  4. 4.

    Yap HY, Yap BS, Tashima CK, et al. Meningeal carcinomatosis in breast Cancer. Cancer 1978; 42: 283–6

  5. 5.

    Rosen S, Aisner J, Makuch R, et al. Carcinomatous leptomeningitis in small cell lung cancer: a clinicopathological review of the National Cancer Institute experience. Medicine 1982; 61: 45–53

  6. 6.

    Fine HA, Mayer RJ. Primary central nervous system lymphoma. Ann Intern Med 1993; 119: 1093–104

  7. 7.

    Kaatsch P, Rickert CH, Kuehl J, et al. Population-based epidemiologic data on brain tumors in German children. Cancer 2001 Dec; 92(12): 3155–64

  8. 8.

    Kumar R, Tekkök IH, Jones RAC. Intracranial tumours in the first 18 months of life. Childs Nerv Syst 1990; 6(7): 371–4

  9. 9.

    Newton HB. Primary brain tumors: review of etiology, diagnosis, and treatment. Am Fam Physician 1994; 49: 787–97

  10. 10.

    Posner JB, Chernik NL. Intracranial metastases from systemic cancer. Adv Neurol 1978; 19: 575–87

  11. 11.

    Olson ME, Chernik NL, Posner JB. Infiltration of the leptomeninges by systemic cancer: a clinical and pathologic study. Arch Neurol 1974; 30: 122–37

  12. 12.

    Little JR, Dale AJD, Okazaki H. Meningeal carcinomatosis. Arch Neurol 1974; 30: 138–43

  13. 13.

    Balm M, Hammack J. Leptomeningeal carcinomatosis. Arch Neurol 1996 Jul; 53: 626–31

  14. 14.

    Chamberlain MC, Kormanik PA. Prognostic significance of coexistent bulky metastatic nervous system disease in patients with leptomeningeal metastases. Arch Neurol 1997 Nov; 54: 1364–8

  15. 15.

    Chamberlain MC, Kormanik P. Carcinomatous meningitis secondary to breast cancer: predictors of response to combined modality therapy. J Neurooncol 1997; 35: 55–64

  16. 16.

    Chamberlain MC, Kormanik P. Carcinoma meningitis secondary to non-small cell lung cancer. Arch Neurol 1998 Apr; 55: 506–12

  17. 17.

    Boogerd W. Central nervous system metastasis in breast cancer. Radiother Oncol 1996; 40: 5–22

  18. 18.

    Schlegel U, Pels H, Glasmacher A, et al. Combined systemic and intraventricular chemotherapy in primary CNS lymphoma a pilot study. J Neurol Neurosurg Psychiatry 2001; 71: 118–22

  19. 19.

    Chamberlain MC, Kormanik P, Glantz M. Recurrent primary central nervous system lymphoma complicated by lymphomatous meningitis. Oncol Rep 1998; 5: 521–5

  20. 20.

    Pui CH, Mahmoud HH, Rivera GK, et al. Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 1998 Jul; 92(2): 411–5

  21. 21.

    Schmandt S, Kuehl J. Chemotherapy as prophylaxis and treatment of meningeosis in children less than 3 years of age with medulloblastoma. J Neurooncol 1998; 38: 187–92

  22. 22.

    Gökbuget N, Hoelzer D. Meningeosis leukaemica in adult acute lymphoblastic leukaemia. J Neurooncol 1998; 38: 167–80

  23. 23.

    Schrappe M, Reiter A, Riehm HJ. Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia. J Neurooncol 1998; 38: 150–65

  24. 24.

    Reiter A, Schrappe M, Yakisan E, et al. Therapy of non-B-cell malignant non Hodgkin’s lymphoma of childhood and adolescence: an interim analysis of study NHL-BFM 90 (Pt II). Klin Paediatr 1994 Jul/Aug; 206: 234–41

  25. 25.

    Kuehl J, Kortmann RD, Mittler U, et al. Medulloblastom: Ergebnisse der Therapiestudie HIT’91 und Pilotstudie HITSKK’92: Konsequenzen für die Folgestudie HIT-Med’ 99. Monatsschr Kinderheilkd 1999 Oct; 147(10): 987

  26. 26.

    Levin VA, Patlak CS, Landahl HD. Heuristic modeling of drug delivery to malignant brain tumors. J Pharmacokinet Biopharm 1980; 8: 257–96

  27. 27.

    Blasberg RG, Patlak C, Fenstermacher JD. Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion. J Pharmacol Exp Ther 1975; 195: 73–83

  28. 28.

    Regina A, Demeule M, Laplante A, et al. Multidrug resistance in brain tumors: roles of the blood-brain barrier. Cancer Metastases Rev 2001; 20: 13–25

  29. 29.

    Bart J, Groen HJ, Hendrikse NH, et al. The blood-brain-barrier and oncology: new insights into function and modulation. Cancer Treat Rev 2000 Dec; 26(6): 449–62

  30. 30.

    Ghersi-Egea JF, Strazielle N. Brain drug delivery, drug metabolism, and multidrug resistance at the choroid pexus. Microsc Res Tech 2001 Jan; 52(1): 83–8

  31. 31.

    Blasberg RG. Methotrexate, cytosine arabinoside, and BCNU concentration in brain after ventriculocisternal perfusion. Cancer Treat Rep 1977 Jul; 61(4): 625–31

  32. 32.

    Cutler RWP, Page L, Galicich J, et al. Formation and absorption of cerebrospinal fluid in man. Brain 1968; 91: 707–20

  33. 33.

    Davson H. The cerebrospinal fluid. In: Lajtha A, editor. Handbook of neurochemistry. Vol. 2. New York: Plenum Press, 1969: 23–48

  34. 34.

    Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev 1999; 25: 103–19

  35. 35.

    Courchesne E, Chisum HJ, Townsend J, et al. Normal brain development and aging: quantitative analysis at in vivo MR imaging in healthy volunteers. Radiology 2000; 216: 672–82

  36. 36.

    Wood JH, Poplack DG, Bleyer WA, et al. Primate model for long-term study of intraventricularly or intrathecally administered drugs and intracranial pressure. Science 1977 Feb; 195(4277): 499–501

  37. 37.

    Poplack DG, Bleyer WA, Wood JH, et al. A primate model for study of methotrexate pharmacokinetics in the central nervous system. Cancer Res 1977 Jul; 37 (7 Pt 1): 1982–5

  38. 38.

    Balis FM, Blaney SM, McCully CL, et al. Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration. Cancer Chemother Pharmacol 2000; 45: 259–64

  39. 39.

    Blaney SM, Poplack DG. New cytotoxic drugs for intrathecal administration. J Neurooncol 1998; 38: 219–23

  40. 40.

    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 May; 51(5): 835–42

  41. 41.

    Bleyer WA, Poplack DG. Prophylaxis and treatment of leukaemia in the central nervous system and other sanctuaries. Semin Oncol 1985 Jun; 12(2): 131–48

  42. 42.

    Blaney SM, Poplack DG, Godwin K, et al. Effect of body position on ventricular CSF methotrexate concentration following intralumbar administration. J Clin Oncol 1995 Jan; 13(1): 177–9

  43. 43.

    Berweiler U, Krone A, Tonn JC. Reservoir systems for intraventricular chemotherapy. J Neurooncol 1998; 38: 141–3

  44. 44.

    Ommaya AK. Subcutaneous reservoir and pump for sterile access to ventricular cerebrospinal fluid. Lancet 1963; II: 983–4

  45. 45.

    Sundaresan N, Suite ND. Optimal use of the ommaya reservoir in clinical oncology. Oncology 1989; 3: 15–22

  46. 46.

    Obbens EA, Leavens ME, Beal JW, et al. Ommaya reservoirs in 387 cancer patients: a 15-year experience. Neurology 1985 Sep; 35: 1274–8

  47. 47.

    Chamberlain MC, Kormanik PA, Barbara D. Complications associated with intraventricular chemotherapy in patients with leptomeningeal metastases. J Neurosurg 1997; 87: 694–9

  48. 48.

    Balis FM, Poplack DG. Central nervous system pharmacology of antileukemic drugs. Am J Pediatr Hematol Oncol 1989; 11(1): 74–86

  49. 49.

    Posner JB. Reservoirs for intraventricular chemotherapy [letter]. N Engl J Med 1973 Jan; 288(4): 212

  50. 50.

    Bakshi S, North RB. Implantable pumps for drug delivery to the brain. J Neurooncol 1995; 26: 133–9

  51. 51.

    Dakhil S, Ensminger W, Kindt G, et al. Implanted system for aventricular drug infusion in central nervous system tumors. Cancer Treat Rep 1981 May/Jun; 65(5–6): 401–11

  52. 52.

    Sipos EP, Brem H. New delivery systems for brain tumor therapy. Neurol Clin 1995 Nov; 13(4): 813–25

  53. 53.

    Blasberg RG, Patlak CS, Shapiro WR. Distribution of methotrexate in the cerebrospinal fluid and brain after intraventricular administration. Cancer Treat Rep 1977 Jul; 61(4): 633–41

  54. 54.

    Czech T, Reinprecht A, Dietrich W, et al. Reversible occlusion shunt for intraventricular chemotherapy in shunt-dependent brain tumor patients. Pediatr Hematol Oncol 1997; 14: 375–80

  55. 55.

    Chamberlain MC. Radiosiotope CSF flow studies in leptomeningeal metastases. J Neurooncol 1998 Jun-Jul, 38(2–3): 135–40

  56. 56.

    Chamberlain MC. Spinal 111Indium-DTPA CSF flow studies in leptomeningeal metastasis. J Neurooncol 1995; 25(2): 135–41

  57. 57.

    Giannone L, Greco FA, Hainsorth JD. Combination intraventricular chemotherapy for meningeal neoplasia. J Clin Oncol 1986 Jan; 4(1): 68–73

  58. 58.

    Schrappe M, Reiter A, Zimmermann M, et al. Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Leukemia 2000; 14: 2205–22

  59. 59.

    Trump DL, Grossmann SA, Thompson G, et al. Treatment of neoplastic meningitis with intraventricular thiotepa and methotrexate. Cancer Treat Rep 1982 Jul; 66(7): 1549–51

  60. 60.

    Yap HY, Yap BS, Rasmussen S, et al. Treatment for meningeal carcinomatosis in breast cancer. Cancer 1982; 49: 219–22

  61. 61.

    Allegra CJ. Antifolates. In: Chabner BA, Collins JM, editors. Cancer chemotherapy: principles and practice. Philadelphia (PA): JB Lippincott Co., 1990: 110–53

  62. 62.

    Bleyer WA. Clinical pharmacology of intrathecal methotrexate. II: an improved dosage regimen derived from age-related pharmacokinetics. Cancer Treat Rep 1977; 61: 1419–25

  63. 63.

    Bleyer WA, Caccia PF, Sather HN, et al. Reduction in central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen. J Clin Oncol 1983 May; 1(5): 317–25

  64. 64.

    Bleyer WA, Dedrick RL. Clinical pharmacology of intrathecal methotrexate. I: pharmacokinetics in non-toxic patients after lumbar injection. Cancer Treat Rep 1977; 61: 703–8

  65. 65.

    Hryniuk WM, Bertino JR. Treatment of leukemia with large doses of methotrexate and folinic acid: clinical-biochemical correlates. J Clin Invest 1969; 48: 2140–55

  66. 66.

    Pinedo HM, Chabner BA. Role of drug concentration, duration of exposure, and endogenous metabolites in determining methotrexate cytotoxicity. Cancer Treat Rep 1977 Jul; 61(4): 709–15

  67. 67.

    Bleyer WA, Poplack DG. Clinical studies on the central-nervous-system pharmacology of methotrexate. In: Pinedo HM, editor. Clinical pharmacology of antineoplastic drugs. Amsterdam: Elsevier/North-Holland Biomedical, 1978: 115–31

  68. 68.

    Shapiro WR, Young DF, Metha BM. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 1975; 293: 161–6

  69. 69.

    Bleyer WA. Intrathecal methotrexate versus central nervous system leukemia. Cancer Drug Deliv 1984; 1: 157–67

  70. 70.

    Bleyer WA, Poplack DG. Intraventricular versus intralumbar methotrexate for central-nervous-system leukaemia: prolonged remission with the ommaya reservoir. Med Pediatr Oncol 1979; 6: 207–13

  71. 71.

    Poplack DG, Bleyer WA, Pizzo PA. Experimental approaches to the treatment of CNS leukaemia. Am J Pediatr Hematol Oncol 1979; 1(2): 141–9

  72. 72.

    Morikawa N, Mori T, Kawashima H, et al. Pharmacokinetics of nimustine, methotrexate, and cytosine arabinoside during cerebrospinal fluid perfusion chemotherapy in patients with disseminated brain tumours. Eur J Clin Pharmacol 1998; 54: 415–20

  73. 73.

    Nakagawa H, Fujita T, Kubo S, et al. Ventriculolumbar perfusion chemotherapy with methotrexate and cytosine arabinoside for meningeal carcinomatosis: a pilot study in 13 patients. Surg Neurol 1996; 4: 256–64

  74. 74.

    Djerassi I, Kim JS, Shulman K. High-dose methotrexate-citrovorum factor rescue in the management of brain tumors. Cancer Treat Rep 1977 Jul; 61(4): 691–4

  75. 75.

    Fujimoto T, Kagaku Ryoko GT. Pharmacokinetics of intrathecal chemotherapy and clinical problems. Gan To Kagaku Ryoho 1984 Aug; 11(8): 1536–42

  76. 76.

    Ettinger LJ, Chervinsky DS, Freeman AI, et al. Pharmacokinetics of methotrexate following intravenous and intraventricular administration in acute lymphocytic leukemia and Non-Hodgkin’s lymphoma. Cancer 1982; 50: 1676–82

  77. 77.

    Glantz MJ, Cole BF, Recht L, et al. High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer, is intrathecal chemotherapy necessary? J Clin Oncol 1998 Apr; 16(4): 1561–7

  78. 78.

    Pitman SW, Frei E. Weekly methotrexate-calcium leucovorin rescue: effect of alkalinization on nephrotoxicity; pharmacokinetics in the CNS; and use in CNS non-Hodgkin’s lymphoma. Cancer Treat Rep 1977 Jul; 61(4): 695–701

  79. 79.

    Borsi JD, Moe PJ. New aspects of clinical and cellular pharmacodynamics of methotrexate with special emphasis on its role in the treatment of acute lymphoblastic leukaemia in children. Acta Paediatr Scand Suppl 1987; 341: 1–31

  80. 80.

    Bode U, Magrath IT, Bleyer WA, et al. Active transport of methotrexate from cerebrospinal fluid in humans. Cancer Res 1980 Jul; 40: 2184–7

  81. 81.

    Strother DR, Glynn-Bernhart A, Kovnar E, et al. Variability in the disposition of intraventricular methotrexate: a proposal for rational dosing. J Clin Oncol 1989; 11: 1741–7

  82. 82.

    Bonoke RS, Cheda G, Bremer A. Inhibition of renal transport of MTX by probenecid. Cancer Res 1975; 35: 110–6

  83. 83.

    Salzer W, Widemann B, McCully C, et al. Effect of probenecid on ventricular cerebrospinal fluid methotrexate pharmacokinetics after intralumbar administration in nonhuman primates. Cancer Chemother Pharmacol 2001; 48: 235–40

  84. 84.

    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 Jan; 43: 435–8

  85. 85.

    Duffner PK, Cohen ME, Brecher ML, et al. CT abnormalities and altered methotrexate clearance in children with CNS leukaemia. Neurology 1984 Feb; 34: 229–33

  86. 86.

    Miller KT, Wilkinson DS. Pharmacokinetics of methotrexate in the cerebrospinal fluid after intracerebroventricular administration in patients with meningeal carcinomatosis and altered cerebrospinal fluid flow dynamics. Ther Drug Monit 1989; 11(3): 231–7

  87. 87.

    Bleyer WA, Nelson JA, Kamen BA. Accumulation of methotrexate in systemic tissues after intrathecal administration. J Pediatr Hematol Oncol 1997; 19(6): 530–2

  88. 88.

    Ettinger LJ. Pharmacokinetics and biochemical effects of a fatal intrathecal MTX overdose. Cancer 1982; 50: 444–50

  89. 89.

    Addiego JE, Ridgway D, Bleyer WA. The acute management of intrathecal MTX overdose: pharmacologic rationale and guidelines. J Pediatr 1981; 98: 825–8

  90. 90.

    O’Marcaigh AS, Johnson CM, Smithson WA, et al. Successful treatment of intrathecal overdose by using ventriculolumbar perfusion and intrathecal instillation of carboxypeptidase G2. Mayo Clin Proc 1996 Feb; 71: 161–5

  91. 91.

    Jardine LF, Ingram LC, Bleyer WA. Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol 1996 Aug; 18(3): 302–4

  92. 92.

    Laborit HM. The role of folic acid in central nervous system physiology. In: Botez MI, Reynolds EH, editors. Folic acid in neurology, psychiatry and internal medicine. New York: Raven Press, 1979: 249–63

  93. 93.

    Sherwood RF, Melton RG, Alwan SM, et al. Purification and properties of carboxypeptidase-G2 from Pseudomonas sp. strain RS-16. Eur J Biochem 1985; 148: 447–53

  94. 94.

    Adamson PC, Balis FM, McCully CL, et al. Rescue of experimental intrathecal methotrexate overdose with carboxypeptidase-G2. J Clin Oncol 1991 Apr; 9(4): 670–4

  95. 95.

    NCI clinical study 92-C-0137: a trial of carboxypeptidase-G2 (CPDG2) for the management of patients with intrathecal methotrexate overdose [online]. Available from URL: [Accessed 2004 Nov 3]

  96. 96.

    Chabner BA. Cytidine analogues. In: Chabner BA, Collins JM, editors. Cancer chemotherapy: principles and practice. Philadelphia (PA): JB Lippincott Co., 1990: 154–79

  97. 97.

    Haaxma-Reiche H, Daenen S, Witteveen RJW. Experiences with the Ommaya reservoir for prophylaxis and treatment of the central nervous system in adult acute myelocytic leukemia. Blut 1988; 57: 351–5

  98. 98.

    Esteva FJ, Soh LT, Holmes FA, et al. Phase II trial and pharmacokinetic evaluation of cytosine arabinoside for leptomeningeal metastases from breast cancer. Cancer Chemother Pharmacol 2000; 46: 382–6

  99. 99.

    Creutzig U, Ritter J, Zimmermann M, et al. Improved results in high-risk pediatric acute myeloid leukemia patients after intensification with high-dose cytarabine/mitoxantrone: results of study acute myeloid leukemia-Berlin-Frankfurt-Münster 93. J Clin Oncol 2001 May; 19(10): 2705–13

  100. 100.

    Schrappe M, Reiter A, Sauter S, et al. Concept and interim analysis of trial ALL-BFM 90 for the treatment of children and adolescents with acute lymphoblastic leukemia: significance of therapy response in peripheral blood and bone marrow. Klin Pädiatr 1994; 206: 208–21

  101. 101.

    Zimm S, Collins JM, Miser J, et al. Cytosine arabinoside cerebrospinal fluid kinetics. Clin Pharmacol Ther 1984 Jun; 35: 826–30

  102. 102.

    Graham FL, Whitmore GF. The effect of 1-β-D-arabinofuranosyl-cytosine on growth, viability, and DNA synthesis of mouse L-cells. Cancer Res 1970; 30: 2627–35

  103. 103.

    Ho DHW. Potential advances in the clinical use of arabinosyl cytosine. Cancer Treat Rep 1977 Jul; 61(4): 717–22

  104. 104.

    Békássy AN, Liliemark J, Garwicz S, et al. Pharmacokinetics of cytosine arabinoside in cerebrospinal fluid and of its metabolite in leukemic cells. Med Pediatr Oncol 1990; 18: 136–42

  105. 105.

    Plunkett W, Iacoboni S, Estey E, et al. Pharmacologically directed ARA-C therapy for refractory leukemia. Semin Oncol 1985; 12 Suppl. 3: 20–30

  106. 106.

    Moser AM, Adamson PC, Gillespie AJ, et al. Intraventricular concentration times time (C × T) methotrexate and cytarabine for patients with recurrent meningeal leukemia and lymphoma. Cancer 1999; 85: 511–6

  107. 107.

    Ho DHW. Distribution of kinase and deaminase of 1-β-D-arabinofuranosylcytosine in tissues of man and mouse. Cancer Res 1973; 33: 2816–20

  108. 108.

    Hande KR, Stein RS, McDonough DA, et al. Effects of highdose cytarabine. Clin Pharmacol Ther 1982; 31: 669–74

  109. 109.

    Slevin ML, Piali EM, Aherne GW, et al. The pharmacokinetics of cytosine arabinoside in the plasma and cerebrospinal fluid during conventional and high-dose therapy. Med Pediatr Oncol 1982; 1: 157–68

  110. 110.

    Breithaupt H, Pralle H, Eckhardt T, et al. Clinical results and pharmacokinetics of high-dose cytosine arabinoside (HD-ARA-C). Cancer 1982; 50: 1248–57

  111. 111.

    Spector R. Pharmacokinetics and metabolism of cytosine arabinoside in the central nervous system. J Pharmacol Exp Ther 1982; 222(1): 1–6

  112. 112.

    Groothuis DR, Benalcazar H, Allen CV, et al. Comparison of cytosine arabinoside to rat brain by intravenous, intrathecal, intraventricular and intraparenchymal routes of administration. Brain Res 2000; 856: 281–90

  113. 113.

    Swain SM, Lippman ME. Endocrine therapies of cancer. In: Chabner BA, Collins JM, editors. Cancer chemotherapy: principles and practice. Philadelphia (PA): JB Lippincott Co., 1990: 59–109

  114. 114.

    Pels H, Deckert-Schlüter M, Glasmacher A, et al. Primary central nervous system lymphoma: a clinicopathological study of 28 cases. Hematol Oncol 2000; 18: 21–32

  115. 115.

    Sullivan MP, Humphrey GB, Vietti TH, et al. Combination intrathecal (IT) therapy for meningeal leukemia: two vs three drugs. Proc Am Assoc Cancer Res 1975; 16: 85

  116. 116.

    Belasco JB, Goldwein JW, Simms S, et al. Hypofractionated moderate dose radiation, intrathecal chemotherapy, and repetitive reinduction/reconsolidation systemic therapy for central nervous system relapse of acute lymphoblastic leukemia in children. Med Pediatr Oncol 2000; 34: 125–31

  117. 117.

    Balis FM, Lester CM, Chrousos GP, et al. Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to the prevention of meningeal leukemia. J Clin Oncol 1987 Feb; 5(2): 202–7

  118. 118.

    Colvin M, Chabner BA. Alkylating agents. In: Chabner BA, Collins JM, editors. Cancer chemotherapy: principles and practice. Philadelphia (PA): JB Lippincott Co., 1990: 276–313

  119. 119.

    Levin VA, Vestnys PS, Edwards MS, et al. Improvement in survival by sequential therapies in the treatment of recurrent medulloblastomas. Cancer 1983; 51: 3164–70

  120. 120.

    Witham TF, Fukui MB, Meltzer CC, et al. Survival of patients with high grade glioma treated with intrathecal thiotriethylenephosphoramide for ependymal or leptomeningeal gliomatosis. Cancer 1999; 86: 1347–53

  121. 121.

    Strong JM, Collins JM, Lester C, et al. Pharmacokinetics of intraventricular and intravenous N,N’,N”-triethylenethiophosphoramide (thiotepa) in rhesus monkeys and humans. Cancer Res 1986 Dec; 46: 6101–4

  122. 122.

    Heidemann RL, Cole DE, Balis F, et al. Phase I and pharmacokinetic evaluation of thiotepa in the cerebrospinal fluid and plasma of pediatric patients: evidence of dose-dependent plasma clearance of thiotepa. Cancer Res 1989 Feb; 49: 736–41

  123. 123.

    Khan AH, Driscoll JS. Potential central nervous system antitumor agents: aziridinylbenzoquinones. J Med Chem 1976; 19: 313–7

  124. 124.

    Berg SL, Balis FM, Zimm S, et al. Phase I/II trial and pharmacokinetics of intrathecal diaziquone in refractory meningeal malignancies. J Clin Oncol 1992 Jan; 10(1): 143–8

  125. 125.

    Zimm S, Collins JM, Curt GA, et al. Cerebrospinal fluid pharmacokinetics of intraventricular and intravenous aziridinylbenzoquinone. Cancer Res 1984 Apr; 44: 1698–701

  126. 126.

    Kim S, Kim DJ, Geyer MA, et al. Multivesicular liposomes containing 1-β-D-arabinofuranosylcytosine for slow-release intrathecal therapy. Cancer Res 1987; 47: 3935–7

  127. 127.

    Kim S, Chatelut E, Kim JC, et al. Extended CSF cytarabine exposure following intrathecal administration of DTC 101. J Clin Oncol 1993 Nov; 11(11): 2186–93

  128. 128.

    Chamberlain MC, Kormanik P, Howell SB, et al. Pharmacokinetics of intralumbar DTC-101 for the treatment of leptomeningeal metastases. Arch Neurol 1995 Sep; 52: 912–7

  129. 129.

    Glantz MJ, Lafollette S, Jaeckle KA, et al. Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 1999 Oct; 17(10): 3110–6

  130. 130.

    Glantz MJ, Jaeckle KA, Chamberlain MC, et al. A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepotCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 1999; 5: 3394–402

  131. 131.

    McCormack JJ, Johns DG. Purine and purine nucleoside antimetabolites. In: Chabner BA, Collins JM, editors. Cancer chemotherapy: principles and practice. Philadelphia (PA): JB Lippincott Co., 1990: 234–52

  132. 132.

    Adamson PC, Balis FM, Arndt CA, et al. Intrathecal 6-mercaptopurine: preclinical pharmacology, phase I/II trial, and pharmacokinetic study. Cancer Res 1991 Nov; 51(22): 6079–83

  133. 133.

    Hayder S, Lafolie P, Bjork O, et al. 6-Mercaptopurine in cerebrospinal fluid during oral maintenance therapy of children with acute lymphoblastic leukemia. Med Oncol Tumor Pharmacother 1988; 5(3): 187–9

  134. 134.

    Zimm S, Ettinger LJ, Holcenberg JS, et al. Phase I and clinical pharmacological study of mercaptopurine administered as a prolonged intravenous infusion. Cancer Res 1985 Apr; 45(4): 1869–73

  135. 135.

    Covell DG, Narang PK, Poplack DG. Kinetic model for disposition of 6-mercaptopurine in monkey plasma and cerebrospinal fluid. Am J Physiol 1985 Feb; 248 (2 Pt 2): R147–56

  136. 136.

    Recht LD, Glantz MJ, Meitner P, et al. Unexpected in vitrochemosensitivity of malignant gliomas to 4-hydroxyperoxy-cyclophosphamide (4-HC). J Neurooncol 1998; 36: 201–8

  137. 137.

    Fuchs HE, Archer GE, Colvin OM, et al. Activity of intrathecal 4-hydroperoxycyclophosphamide in a nude rat model of human neoplastic meningitis. Cancer Res 1990; 50(6): 1954–9

  138. 138.

    Friedman HS, Colvin OM, Skapek SX, et al. Experimental chemotherapy of human medulloblastoma cell lines and transplantable xenografts with bifunctional alkylating agents. Cancer Res 1988; 48: 4189–95

  139. 139.

    DeFabritiis P, Bregni M, Lupton J, et al. Elimination of clonogenic Burkitt’s lymphoma cells from human bone marrow using 4-hydroperoxycyclophosphamide in combination with monoclonal antibodies and complement. Blood 1985; 65: 1064–70

  140. 140.

    Kubota T, Hanatani Y, Tsuyuk K, et al. Antitumor effect and metabolic activation of hydroperoxycyclophosphamide in the human breast adenocarcinoma (MX-1) nude mouse system. Gann 1983; 74: 437–44

  141. 141.

    Arndt CA, Colvin OM, Balis FM, et al. Intrathecal administration of 4-hydroperoxycyclophosphamide in rhesus monkeys. Cancer Res 1987 Nov; 47(22): 5932–4

  142. 142.

    Phillips PC, Than TT, Cork LC, et al. Intrathecal 4-hydroperoxycyclophosphamide: neurotoxicity, cerebrospinal fluid pharmacokinetics, and antitumor activity in a rabbit model of VX2 leptomeningeal carcinomatosis. Cancer Res 1992 Nov; 52(22): 6168–74

  143. 143.

    Slavc I, Schuller E, Czech T, et al. Intrathecal mafosfamide therapy for pediatric brain tumors with meningeal dissemination. J Neurooncol 1998; 38: 213–8

  144. 144.

    Friedman HS, Oakes WJ. New therapeutic options in the management of childhood brain tumors. Oncology 1992 May; 6(5): 27–36

  145. 145.

    van Maanen JMS, Retèl J, de Vries J, et al. Mechanism of action of antitumor drug etoposide: a review. J Natl Cancer Inst 1988; 80: 1526–33

  146. 146.

    Dunkel IJ, Boyett JM, Yates A, et al. High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. Children’s Cancer Group. J Clin Oncol 1998; 16: 222–8

  147. 147.

    Tomlinson FH, Lihou MG, Smith PJ. Comparison of in vitroactivity of epipodophyllotoxins with other chemotherapeutic agents in human medulloblastomas. Br J Cancer 1991; 64: 1051–9

  148. 148.

    Kiya K, Uozumi T, Ogasawara H, et al. Penetration of etoposide into human malignant brain tumors after intravenous and oral administration. Cancer Chemother Pharmacol 1992; 29: 339–42

  149. 149.

    Postmus PE, Holthuis JJ, Haaxma RH, et al. Penetration of VP 16-213 into cerebrospinal fluid after high-dose intravenous administration. J Clin Oncol 1984; 2: 215–20

  150. 150.

    Hande KR, Wedlund PJ, Noone RM, et al. Pharmacokinetics of high-dose etoposide (VP-16-213) administered to cancer patients. Cancer Res 1984; 44: 379–82

  151. 151.

    Henwood JM, Brogden RN. Etoposide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in combination chemotherapy of cancer. Drugs 1990; 39: 438–90

  152. 152.

    Van der Gaast A, Sonneveld P, Mans DRA, et al. Intrathecal administration of etoposide in the treatment of malignant meningitis: feasibility and pharmacokinetic data. Cancer Chemother Pharmacol 1992; 29: 335–7

  153. 153.

    Fleischhack G, Reif S, Hasan C, et al. Feasibility of intraventricular administration of etoposide in patients with metastatic brain tumors. Br J Cancer 2001; 84(11): 1453–9

  154. 154.

    Slichenmyer WJ, Rowinsky EK, Donehower RC, et al. The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 1993; 85: 271–91

  155. 155.

    Verschraegen CF, Jaeckle K, Giovanella B, et al. Alternative administration of camptothecin analogues. Ann N Y Acad Sci 2000; 922: 237–46

  156. 156.

    Blaney SM, Heideman R, Berg S, et al. Phase I clinical trial of intrathecal topotecan in patients with neoplastic meningitis. J Clin Oncol 2003 Jan; 21(1): 143–7

  157. 157.

    Baker SD, Heideman RL, Crom WR, et al. Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharmacol 1996; 37(3): 195–202

  158. 158.

    Blaney SM, Cole DE, Godwin L, et al. Intrathecal administration of topotecan in nonhuman primates. Cancer Chemother Pharmacol 1995; 6: 121–4

  159. 159.

    Sung C, Blaney SM, Cole DE, et al. A pharmacokinetic model of topotecan clearance from plasma and cerebrospinal fluid. Cancer Res 1994 Oct; 54: 5118–22

  160. 160.

    Levin VA, Chamberlain M, Silver P, et al. Phase I/II study of intraventricular and intrathecal ACNU for leptomeningeal neoplasia. Cancer Chemother Pharmacol 1989; 23(5): 301–7

  161. 161.

    Hori T, Hirao J, Okamoto H, et al. Intrathecal distribution of ACNU by various modes of its administration analyzed by HPLC and autoradiography [in Japanese]. No To Shinkei 1991 Sep; 43(9): 833–41

  162. 162.

    Kochi M, Kuratsu JI, Mihara Y, et al. Ventriculolumbar perfusion of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chlorethyl)-1-nitrosurea hydrochloride. Neurosurgery 1993 Nov; 33(5): 817–23

  163. 163.

    Ushio Y, Kochi M, Kitamura I, et al. Ventriculolumbar perfusion of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chlorethyl)-1-nitrosurea hydrochloride for subarachnoid dissemination of gliomas. J Neurooncol 1998; 38: 207–12

  164. 164.

    Chabner BA. Bleomycin. In: Chabner BA, Collins JM, editors. Cancer chemotherapy: principles and practice. Philadelphia (PA): JB Lippincott Co., 1990: 341–55

  165. 165.

    Hayakawa T, Ushio Y, Morimoto K, et al. Uptake of bleomycin by human brain tumours. J Neurol Neurosurg Psychiatry 1976; 39: 341–9

  166. 166.

    Levin VA, Byrd D, Sikic BI, et al. Central nervous system toxicity and cerebrospinal fluid pharmacokinetics of intraventricularly administered bleomycin in beagles. Cancer Res 1985 Aug; 45: 3810–5

  167. 167.

    Savas A, Arasil E, Batay F, et al. Intracavitary chemotherapy of polycystic craniopharyngeoma with bleomycin. Acta Neurochir (Wien) 1999; 141: 547–9

  168. 168.

    Blasberg RG. Pharmacodynamics and blood brain barrier. Natl Cancer Inst Monogr 1977; 46: 19–27

  169. 169.

    Bleyer WA. Current status of intrathecal chemotherapy for human meningeal neoplasms. Natl Cancer Inst Monogr 1977; 46: 171–8

  170. 170.

    Collins JM. Pharmacokinetics of intraventricular administration. J Neurooncol 1983; 1: 283–91

  171. 171.

    Friedman HS, Archer GE, McLendon RE, et al. Intrathecal melphalan therapy of human neoplastic meningitis in athymic nude rats. Cancer Res 1994 Sep; 54(17): 4710–4

  172. 172.

    Archer GE, Sampson JH, McLendon RE, et al. Intrathecal busulfan treatment of human neoplastic meningitis in athymic nude rats. J Neurooncol 1999; 44(3): 233–41

  173. 173.

    Mizumatsu S, Matsumoto K, Ono Y, et al. Intrathecal chemotherapy with MX2 for treating glioma dissemination in vivo. J Neurooncol 2000; 49: 41–7

  174. 174.

    Egorin MJ, Zuhowski EG, McCully CM, et al. Pharmacokinetics of intrathecal gemcitabine in nonhuman primates. Clin Cancer Res 2002 Jul; 8(7): 2437–42

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The authors wish to thank Michaela Huber for her support in the preparation of this article. This paper was supported by a grant from the Deutsche Kinderkrebsstiftung (German Research Foundation for Cancer in Children). The authors have no conflicts of interest that are directly relevant to the content of this review.

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Correspondence to Dr Gudrun Fleischhack.

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Fleischhack, G., Jaehde, U. & Bode, U. Pharmacokinetics Following Intraventricular Administration of Chemotherapy in Patients with Neoplastic Meningitis. Clin Pharmacokinet 44, 1–31 (2005).

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  • Cytarabine
  • Topotecan
  • Neoplastic Meningitis
  • Primary Malignant Brain Tumour
  • Intraventricular Administration