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Intrathecal Chemotherapy With Antineoplastic Agents in Children

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Abstract

Intrathecal chemotherapy with antineoplastic agents is mainly utilised in children with leukaemia and lymphoma, and in selected brain tumours. In these diseases, intrathecal use is restricted to methotrexate (MTX), cytosine arabinoside (Ara-C) and corticosteroids. A number of other agents are, at the present time, under evaluation.

Intrathecal MTX administered sequentially with systemic high dose MTX infusion prolongs therapeutic cerebral spinal fluid (CSF) levels of the drug. Prolonged therapeutic CSF levels can also be achieved by giving repeated small intrathecal doses of MTX over an extended period in selected patients, with an implanted Ommaya reservoir.

In the CSF, the metabolic inactivation of Ara-C is significantly lower than in plasma with a CSF clearance similar to the rate of CSF bulk flow. A slow-release formulation of Ara-C may be given intrathecally, resulting in a prolonged cytotoxic concentration in the CSF.

CNS relapse and neurotoxicity in patients with acute lymphoblastic leukaemia, especially younger children, may be reduced by using age-related dosing of intrathecal MTX and Ara-C.

Hydrocortisone is used in combination with MTX and Ara-C for so-called ‘triple intrathecal chemotherapy’ in the treatment of meningeal leukaemia. Intrathecal thiotepa does not appear to be advantageous over systemic administration in patients with brain and meningeal leukaemia.

Monoclonal antibodies, reactive with tumour-associated antigens, can be used as delivery systems for chemotherapeutic agents and radionuclides. However, the development of this new approach is currently under evaluation in larger clinical studies.

Neurological adverse effects may be expected with intrathecal chemotherapy and are increased by high dose systemic therapy, concomitant cranial radiotherapy or meningeal infiltration by neoplastic cells.

Inadvertant intrathecal administration of antineoplastic agents that are indicated for systemic administration only, is dangerous and may result in a fatal outcome.

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References

  1. Hustu HO, Aur RJ, Verzosa MS, et al. Prevention of central nervous system leukemia by irradiation. Cancer 1973; 32: 585–97

    Article  PubMed  CAS  Google Scholar 

  2. Holland JF, Glidewell O. Chemotherapy of acute lymphocytic leukaemia of childhood. Cancer 1972; 30: 1480–7

    Article  PubMed  CAS  Google Scholar 

  3. Littman P, Coccia P, Bleyer WA, et al. Central nervous system prophylaxis in children with low risk acute lymphoblastic leukemia. Int J Radiat Oncol Biol Phys 1987; 13: 1443–9

    Article  PubMed  CAS  Google Scholar 

  4. Buhrer C, Henze G, Hofmann J, et al. Central nervous system relapse prevention in 1165 standard-risk children with acute lymphoblastic leukemia in five BFM trials. Haematol Blood Transfus 1990; 33: 500–3

    PubMed  CAS  Google Scholar 

  5. Ottensmeier H, Kuhl J. Pilot trial HIT-SKK’87/HIT-SKK’92: a retrospective neuropsychological study in children less than 3 years of age with medulloblastoma [abstract no. 15]. Proceedings of the 9th International Symposium on Pediatric Neurooncology; 2000 Jun 11–14; San Francisco, 64

  6. Oldendorf WH. The blood-brain barrier. In: Lajtha A. editor. Handbook of neurochemistry. Vol. 7. New York: Plenum Press, 1984: 485–99

    Google Scholar 

  7. Lane NJ. A comparison of the construction of intercellular junctions in the CNS of vertebrates. Trend Neurosci 1984; 7: 95–9

    Article  Google Scholar 

  8. Brightman MW. Morphology of blood-brain interfaces. Exp Eye Res 1977; 25 Suppl.: 1–25

    Article  PubMed  Google Scholar 

  9. Crone C. The blood-brain barrier: facts and questions. In: Siesjo BK, Sorensen SC, editors. Ion homeostasis of the brain. Copenhagen: Munksgaard, 1971: 52–62

    Google Scholar 

  10. Sobue K, Yamamoto N, Yoneda K, et al. Induction of blood-brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neurosci Res 1999; 35(2): 155–64

    Article  PubMed  CAS  Google Scholar 

  11. Fardel O, Lecureur V, Guillouzo A. The P-glycoprotein multidrug transporter. Gentile Pharmacol 1996; 27(8): 1283–91

    Article  CAS  Google Scholar 

  12. Schinkel AH. Pharmacological insights from P-glycoprotein knockout mice. Int J Clin Pharmacol Ther 1998; 36(1): 9–13

    PubMed  CAS  Google Scholar 

  13. Nichol CA. Pharmacokinetics selectivity of action related to physiochemical properties and kinetic patterns of anticancer drugs. Cancer 1977; 40: 519–28

    Article  PubMed  CAS  Google Scholar 

  14. Levin VA, Wilson CB. Chemotherapy. The agents in current use. Semin Oncol 1975; 2: 63–7

    PubMed  CAS  Google Scholar 

  15. Blasberg RG. Pharmacodynamics and the blood-brain barrier in modern concepts in brain tumor therapy: laboratory and clinical investigations. J Natl Cancer Inst 1977; 46: 19–27

    CAS  Google Scholar 

  16. Pardridge WM, Oldendorf WH, Cancilla P, et al. Blood-brain barrier: interface between internal medicine and the brain. UCLA Conference. Ann Intern Med 1986; 105: 82–95

    PubMed  CAS  Google Scholar 

  17. Collins JM. Regional therapy: an overview. In: Poplack DG, Massimo L, Cornaglia-Ferraris P, editors. The role of pharmacology in pediatric oncology. Boston (MA): Martinus Njihoff, 1987: 125–35

    Chapter  Google Scholar 

  18. Poplack DG, Riccardi R. Pharmacologic approaches to the treatment of central nervous system malignancy. In: Poplack DG, Massimo L, Cornaglia-Ferraris P, editors. The role of pharmacology in pediatric oncology. Boston (MA): Martinus Njihoff, 1987: 137–56

    Chapter  Google Scholar 

  19. Poplack DG, Bleyer WA, Horowitz ME. Pharmacology of antineoplastic agents in cerebrospinal fluid. In: Wood JH, editor. Neurobiology of cerebrospinal fluid. Vol. 1. New York: Plenum Press, 1980; 561–78

    Chapter  Google Scholar 

  20. Aur RJA, Simone JV, Hustu HO, et al. Central nervous system therapy and combination chemotherapy of childhood lymphocytic leukemia. Blood 1971; 37: 272–81

    PubMed  CAS  Google Scholar 

  21. Larson SM, Schall GL, DiChiro G. The influence of previous lumbar puncture and pneumoencephalography on the incidence of unsuccessful radioisotope cisternography. J Nucl Med 1971; 12: 555–7

    PubMed  CAS  Google Scholar 

  22. Bleyer WA, Poplack DG, Simon RM, et al. Concentration x time methotrexate via a subcutaneous reservoir: a less toxic regimen for intraventricular chemotherapy of central nervous system neoplasms. Blood 1978; 51: 835–42

    PubMed  CAS  Google Scholar 

  23. Echelberger CK, Riccardi R, Bleyer A, et al. Influence of body position on ventricular cerebrospinal fluid methotrexate concentration following intralumbar administration [abstract]. Proceedings of the American Society of Clinical Oncology; 1981; 22: 365

    Google Scholar 

  24. Ommaya AK. Implantable devices for chronic access and drug delivery to the central nervous system. Cancer Drug Deliv 1984; 1: 169–79

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  26. Blasberg RG, Patlak C, Fernstermacher JD. Intrathecal chemotherapy: brain tissue profiles after ventriculo-cisternal perfusion. J Pharmacol Exp Ther 1975; 195: 73–83

    PubMed  CAS  Google Scholar 

  27. Lippens RJJ. Methotrexate II: use in pediatric chemotherapy. Am J Pediatr Hematol Oncol 1984; 6(4): 397–413

    Article  PubMed  CAS  Google Scholar 

  28. Grossman SA, Trump DL, Chen DCP, et al. Cerebrospinal fluid flow abnormalities in patients with neoplastic meninigitis: an evaluation using 111Indium-DTPA ventriculography. Am J Med 1982; 73: 641–7

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  30. Bleyer WA, Drake JC, Chabner BA. Neurotoxicity and elevated cerebrospinal fluid methotrexate concentration in menigeal leukemia. N Engl J Med 1973; 289: 770–3

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  32. Iacoangeli M, Roselli R, Pagano L, et al. Intrathecal chemotherapy for treatment of overt meningeal leukemia: comparison between intraventricular and traditional intralumbar route. Ann Oncol 1995; 6: 377–82

    PubMed  CAS  Google Scholar 

  33. Lankelma J, Lippens RJJ, Drenthe-Schonk A, et al. Change in transfer rate of methotrexate from spinal fluid to plasma during intrathecal therapy in children and adults. Clin Pharmacokinet 1980; 5: 465–75

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  35. Pinkel D, Woo S. Prevention and treatment of meningeal leukemia in children. Blood 1994; 84(2): 355–66

    PubMed  CAS  Google Scholar 

  36. Lopez JA, Nassif E, Vannicola P, et al. Central nervous system pharmacokinetics of high-dose cytosine arabinoside. J Neurooncol 1985; 3: 119–24

    Article  PubMed  CAS  Google Scholar 

  37. Slevin ML, Piall 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; 10 (Suppl. 1): 157–68

    Article  PubMed  Google Scholar 

  38. Camiener GW, Smith CG. Studies of the enzymatic deamination of cytosine arabinoside. I: enzyme distribution and species specificity. Biochem Pharmacol 1965; 14: 1405–16

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  40. Zimm S, Jerry MC, Miser J, et al. Cytosine arabinoside cerebrospinal fluid kinetics. Clin Pharmacol Ther 1984; 35(6): 826–30

    Article  PubMed  CAS  Google Scholar 

  41. Riccardi A, Servidei T, Lasorella A, et al. High-performance liquid chromatographic assay for cytosine arabinoside and uracil arabinoside in cerebrospinal fluid and plasma. J Chromatogr 1989; 497: 302–7

    Article  PubMed  CAS  Google Scholar 

  42. Kohn FR, Malkmus SA, Brownson EA, et al. Fate of the predominant phospholipid component of DepoFoam drug delivery matrix after intrathecal administration of sustained-release encapsulated cytarabine in rats. Drug Deliv 1998; 5: 143–51

    Article  PubMed  CAS  Google Scholar 

  43. 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; 17(10): 3110–6

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  45. Bleyer WA. Intrathecal depot cytarabine therapy: a welcome addition to a limited armamentarium. Clin Cancer Res 1999; 5: 3349–51

    PubMed  CAS  Google Scholar 

  46. Pullen J, Boyett J, Shuster J, et al. Extended triple intrathecal chemotherapy trial for prevention of CNS relapse in good-risk and poor-risk patients with B-progenitor acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol 1993; 11(5): 839–49

    PubMed  CAS  Google Scholar 

  47. 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; 5(2): 202–7

    PubMed  CAS  Google Scholar 

  48. Jones B, Freeman AI, Shuster JJ, et al. Lower incidence of meningeal leukemia when prednisone is replaced by dexamethasone in the treatment of acute lymphocytic leukemia. Med Pediatr Oncol 1991; 19(4): 269–75

    Article  PubMed  CAS  Google Scholar 

  49. Gomez-Almaguer D, Gonzalez-Llano O, Montemayor J, et al. Dexamethasone in the treatment of meningeal leukemia. Am J Hematol 1995; 49(4): 353–4

    Article  PubMed  CAS  Google Scholar 

  50. Kroin JS, Schaefer RB, Penn RD. Chronic intrathecal administration of dexamethasone sodium phosphate: pharmacokinetics and neurotoxicity in an animal model. Neurosurgery 2000; 46(1) 178–82

    Article  PubMed  CAS  Google Scholar 

  51. Blaney SM, Balis FM, Poplack DG. Current pharmacological treatment approaches to central nervous system leukaemia. Drugs 1991; 41(5): 702–16

    Article  PubMed  CAS  Google Scholar 

  52. 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; 46 (12 Pt 1): 6101–4

    PubMed  CAS  Google Scholar 

  53. Adamson PC, Balis FM, Arndt CA, et al. Intrathecal 6-mercaptopurine: preclinical pharmacology, phase I/II trial, and pharmacokinetics study. Cancer Res 1991; 51(15): 6079–83

    PubMed  CAS  Google Scholar 

  54. Blaney SM, Poplack DG. New cytotoxic drugs for intrathecal administration. J Neurooncol 1998; 38(2–3): 219–23

    Article  PubMed  CAS  Google Scholar 

  55. Sampson JH, Archer GE, Villavicencio AT, et al. Treatment of neoplastic meningitis with intrathecal temozolomide. Clin Cancer Res 1999; 5: 1183–8

    PubMed  CAS  Google Scholar 

  56. Brown MT, Coleman RE, Friedman AH, et al. Intrathecal 13 1I-labeled antitenascin monoclonal antibody 81C6 treatment of patients with leptomenigeal neoplasms or primary brain tumor resection cavities with subarachnoid communication: phase I trial results. Clin Cancer Res 1996; 2: 963–72

    PubMed  CAS  Google Scholar 

  57. Kemshead JT, Hopkins K, Pizer B, et al. Dose escalation with repeated intrathecal injections of 13 1I-labelled mabs for the treatment of central nervous system malignancies. Br J Cancer 1998; 77(12): 2324–30

    Article  PubMed  CAS  Google Scholar 

  58. MacDonald DR. Neurologic complications of chemotherapy. Neurol Clin 1991; 9(4): 955–67

    PubMed  CAS  Google Scholar 

  59. Kaplan RS, Wiernik PH. Neurotoxicity of antineoplastic drugs. Semin Oncol 1982; 9(1): 103–30

    PubMed  CAS  Google Scholar 

  60. Saiki H, Thompson S, Smith F, et al. Paraplegia following intrathecal chemotherapy. Cancer 1975; 35: 306–18

    Article  Google Scholar 

  61. Price RA, Jamieson PA. The central nervous system in childhood leukemia: II. Subacute leukoencephalopathy. Cancer 1975; 35: 306–18

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  64. Trinkle R, Wu JK. Errors involving pediatric patients receiving chemotherapy: a literature review. Med Pediatr Oncol 1996; 26: 344–51

    Article  PubMed  CAS  Google Scholar 

  65. Jakobson AM, Kreuger A, Mortimer O, et al. Cerebrospinal fluid exchange after intrathecal methotrexate overdose: a report of two cases. Acta Paediatr 1992; 81: 359–61

    Article  PubMed  CAS  Google Scholar 

  66. O’Marcaigh AS, Johnson CM, Smithson WA, et al. Successful treatment on intrathecal methotrexate overdose by using ventriculolumbar perfusion and intrathecal instillation of carboxypeptidase G2. Mayo Clin Proc 1996; 71(2): 161–5

    Article  PubMed  Google Scholar 

  67. Eden OB, Goldie W, Wood T, et al. Seizures following intrathecal cytosine arabinoside in young children with acute lymphoblastic leukemia. Cancer 1978; 42: 53–8

    Article  PubMed  CAS  Google Scholar 

  68. Wolff L, Zighelboim J, Gale RP. Paraplegia following intrathecal cytosine arabinoside. Cancer 1979; 43: 83–5

    Article  PubMed  CAS  Google Scholar 

  69. Al Ferayan A, Russell NA, Wohaibi M, et al. Cerebrospinal fluid lavage in the treatment of inadvertent intrathecal vincristine injection. Childs Nerv Syst 1999; 15(2–3): 87–9

    Article  PubMed  CAS  Google Scholar 

  70. Meggs WJ, Hoffman RS. Fatality resulting from intraventricular vincristine administration. J Toxicol Clin Toxicol 1998; 36(3): 243–6

    Article  PubMed  CAS  Google Scholar 

  71. Poplack DG. Massive intrathecal overdose: ‘check the label twice!’. N Engl J Med 1984; 9: 400–2

    Article  Google Scholar 

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Authors and Affiliations

  1. Division of Paediatric Oncology, Catholic University, Largo A. Gemelli 8, 00168, Roma, Italy

    Antonio Ruggiero, Ilaria Lazzareschi &  Riccardo Riccardi

  2. Paediatric Department, Milano Bicocca University, Ospedale S. Gerardo, Monza, Italy

    Valentino Conter, Marina Milani, Ettore Biagi & Paola Sparano

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  1. Antonio Ruggiero
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  2. Valentino Conter
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  3. Marina Milani
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Correspondence to Riccardo Riccardi.

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Ruggiero, A., Conter, V., Milani, M. et al. Intrathecal Chemotherapy With Antineoplastic Agents in Children. Pediatr-Drugs 3, 237–246 (2001). https://doi.org/10.2165/00128072-200103040-00001

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