Journal of Neuro-Oncology

, Volume 7, Issue 3, pp 269–281 | Cite as

Fatal necrotizing encephalopathy complicating treatment of malignant gliomas with intra-arterial BCNU and irradiation: A pathological study

  • Marc K. Rosenblum
  • Jean-Yves Delattre
  • Russell W. Walker
  • William R. Shapiro


We describe the neuropathologic findings at autopsy in six patients who developed a progressive encephalopathy complicating the treatment of malignant gliomas with combined intra-arterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cerebral irradiation. Four brains were free of tumor and one contained a microscopic focus of residual glioma. In only one case was there evidence of tumor progression. A disseminated process characterized by miliary foci of necrosis with mineralizing axonopathy was present in all cases, restricted to the internal carotid distribution of the perfused hemisphere and involving primarily though not exclusively the white matter, which was diffusely and severely edematous. This was combined in 3 cases with a histologically dissimilar, massive necrotizing leukoencephalopathy indistinguishable from pure radionecrosis. Much of the toxicity of this therapy is mediated by vascular injury, but the disseminated necrotizing lesion probably reflects, at least in part, direct neural damage.

Key words

BCNU cerebral irradiation neurotoxicity encephalopathy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Carter SK, Newman JW: Nitrosoureas: 1,3-bis(2-chloroethyl)-1-nitrosourea (NSC-409962; BCNU) and 1-(2chloroethyl)-3-cyclohexyl-1-nitrosourea (NSC-79037; CCNU)-clinical brochure. Cancer Chemother Rep (Part 3) 1: 115–151, 1968Google Scholar
  2. 2.
    Devita VT, Denham C, Davidson JD, Oliverio VT: The physiological disposition of the carcinostatic 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in man and animals. Clin Pharmacol Thera 8: 566–577, 1967Google Scholar
  3. 3.
    Fenstermacher JD, Cowles AL; Theoretic limitations of intracarotid infusions in brain tumor chemotherapy. Cancer Treat Rep 61: 519–526, 1977Google Scholar
  4. 4.
    Collins JM: Pharmacologic rationale for regional drug delivery. J Clin Oncol 2: 498–504, 1984Google Scholar
  5. 5.
    Eckman WW, Patlak CS, Fenstermacher JD: A critical evaluation of the principles governing the advantages of intra-arterial infusion. J Pharmacokinet Biopharmacokinet 2: 257–285, 1974Google Scholar
  6. 6.
    Levin VA, Kabra PM, Freeman-Dove MA: Pharmacokinetics of intracarotid artery 14C-BCNU in the squirrel monkey. J Neurosurg 48: 587–593, 1978Google Scholar
  7. 7.
    Oldendorf WH: A comparison of carotid and venous injection of antitumor agent BCNU. Trans Am Neurol Assoc 100: 225–226, 1975Google Scholar
  8. 8.
    Rosenblum ML, Gerosa MA, Dougherty DV, Wilson CB: Improved treatment of a brain-tumor model. Part 1: Advantages of single- over multiple-dose BCNU schedules. J Neurosurg 58: 177–182, 1983Google Scholar
  9. 9.
    Bullard DE, Bigner SH, Bigner DD: Comparison of intravenous versus intracarotid therapy with 1,3-bis(2-chloroethyl)-1-nitrosourea in a rat brain tumor model. Cancer Res 45: 5240–5245, 1985Google Scholar
  10. 10.
    Yamada K, Bremer AM, West CR, Ghoorah J, Park HC, Takita H: Intra-arterial BCNU therapy in the treatment of metastatic brain tumor from lung carcinoma — a preliminary report. Cancer 44: 2000–2007, 1979Google Scholar
  11. 11.
    Madajewicz S, West CR, Park HC, Ghoorah J, Avellanosa AM, Takita H, Karakousis C, Vincent R, Caracandas J, Jennings E: Phase II study — intra-arterial BCNU therapy for metastatic brain tumors. Cancer 47: 653–657, 1981Google Scholar
  12. 12.
    Grimson BS, Mahaley MS Jr, Dubey HD, Dudka L: Ophthalmic and central nervous system complications following intracarotid BCNU (Carmustine). J Clin Neuroophthalmol 1: 261–264, 1981Google Scholar
  13. 13.
    Greenberg HS, Ensminger WD, Chandler WF, Layton PD, Junck L, Knake J, Vine AK: Intra-arterial BCNU chemotherapy for treatment of malignant gliomas of the central nervous system. J Neurosurg 61: 423–429, 1984Google Scholar
  14. 14.
    Miller DF, Bay JW, Lederman RJ, Purvis JD, Rogers LR, Tomsak RL: Ocular and orbital toxicity following Intracarotid injection of BCNU (Carmustine) and cisplatinum for malignant gliomas. Ophthalmology 92: 402–406, 1985Google Scholar
  15. 15.
    Kupersmith MJ, Frohman LP, Choi IS, Foo SH, Hiesinger E, Berenstein A, Wise A, Carr RE, Ransohoff J: Visual system toxicity following intra-arterial chemotherapy. Neurology 38: 284–289, 1988Google Scholar
  16. 16.
    Kapp J, Vance R, Parker L, Smith RR: Limitations of high dose intra-arterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) chemotherapy for malignant gliomas. Neurosurgery 10: 715–719, 1982Google Scholar
  17. 17.
    Hochberg FH, Pruitt AA, Beck DO, DeBrun G, Davis K: The rationale and methodology for intra-arterial chemotherapy with BCNU as treatment for glioblastoma. J Neurosurg 63: 876–880, 1985Google Scholar
  18. 18.
    Mahaley MS JR, Whaley RA, Blue M, Bertsch L: Central neurotoxicity following intracarotid BCNU chemotherapy for malignant gliomas. J Neuro-Oncol 3: 297–314, 1986Google Scholar
  19. 19.
    Kleinschmidt-DeMasters BK: Intracarotid BCNU leukoencephalopathy. Cancer 57: 1276–1280, 1986Google Scholar
  20. 20.
    Foo SH, Choi IS, Berenstein A, Wise A, Ransohoff J, Koslow M, George A, Lin J, Feigin I, Budzilovich G, Kupersmith M, Hanson R, Lequerica S, Aleksic S, Kricheff I: Supraophthalmic intracarotid infusion of BCNU for malignant glioma. Neurology 36: 1437–1444, 1986Google Scholar
  21. 21.
    Shapiro WR, Green SB: Re-evaluating the efficacy of intraarterial BCNU (letter to the editor). J Neurosurg 66: 313–315, 1987Google Scholar
  22. 22.
    Shapiro WR, Green SB, Burger PC, Selker RG, Van Gilder JD, Robertson JT, Mealey J, Ransohoff J, Mahaley MS (BTCG): A randomized comparison of intraarterial (IA) vs. intravenous (IV) BCNU for patients with malignant glioma (study 8301): interim analysis demonstrating lack of efficacy for IA BCNU. Proc Am Soc Clin Oncol 6: 69, 1987 (Abst).Google Scholar
  23. 23.
    DeWys WD, Fowler EH: Report of vasculitis and blindness after intracarotid injection of 1,3-bis(2-chloroethyl)-1-nitrourea (BCNU; NSC-409962) in dogs. Cancer Chemother Rep 57: 33–40, 1973Google Scholar
  24. 24.
    Omojola MF, Fox AJ, Auer RN, Vinuela FV: Hemorrhagic encephalitis produced by selective non-occlusive Intracarotid BCNU injection in dogs. J Neurosurg 57: 791–796, 1982Google Scholar
  25. 25.
    Crafts DC, Levin VA, Nielsen S: Intracarotid BCNU (NSC-409962): a toxicity study in six rhesus monkeys. Cancer Treat Rep 60: 541–545, 1976Google Scholar
  26. 26.
    Burger PC, Kamenar E, Schold SC, Fay JW, Phillips GL, Herzig GP: Encephalomyelopathy following high-dose BCNU therapy. Cancer 48: 1318–1327, 1981Google Scholar
  27. 27.
    Blacklock JB, Wright DC, Dedrick RL, Blasberg RG, Lutz RJ, Doppman JL, Oldfield EH: Drug streaming during intra-arterial chemotherapy. J Neurosurg 64: 284–291, 1986Google Scholar
  28. 28.
    Lutz RJ, Dedrick RL, Boretos JW, Oldfield EH, Blacklock JB, Doppman JL: Mixing studies during intracarotid artery infusion in an in vitro model. J Neurosurg 64: 277–283, 1986Google Scholar
  29. 29.
    Rubenstein LJ, Herman MM, Long TF, Wilbur JR: Disseminated necrotizing leukoencephalopathy: a complication of treated central nervous system leukemia and lymphoma. Cancer 35: 291–305, 1975Google Scholar
  30. 30.
    Devivo DC, Malas D, Nelson JS, Land VJ: Lcukoencephalopathy in childhood leukemia. Neurology 27: 609–613, 1977Google Scholar
  31. 31.
    Breuer AC, Blank NK, Schoene WC: Multifocal pontine lesions in cancer patients treated with chemotherapy and CNS radiotherapy. Cancer 41: 2112–212, 1978Google Scholar
  32. 32.
    Allen JC, Rosen G, Mehta BM, Horten B: Leukoencephalopathy following high-dose IV methotrexate chemotherapy with leucovorin rescue. Cancer Treat Rep 64: 1261–1273, 1980Google Scholar
  33. 33.
    Shapiro WR, Allen JC, Horten BC: Chronic methotrexate toxicity to the central nervous system. Clin Bull 10: 49–52, 1980Google Scholar
  34. 34.
    Shapiro WR, Chernik NL, Posner JB: Necrotizing encephalopathy following intraventricular instillation of methotrexate. Arch Neurol 28: 96–102, 1973Google Scholar
  35. 35.
    Liu HM, Maurer HS, Vongsvivut S, Conway JJ: Methotrexate encephalopathy — a neuropathologic study. Human Pathol 9: 635–648, 1978Google Scholar
  36. 36.
    Price RA, Jamieson PA: The central nervous system in childhood leukemia II. Subacute leukoencephalopathy. Cancer 35: 306–318, 1975Google Scholar
  37. 37.
    Burger PC, Mahaley Jr MS, Dudka L, Vogel FS: The morphologic effects of radiation administered therapeutically for intracranial gliomas — a postmortem study of 25 cases. Cancer 44: 1256–1272, 1979Google Scholar
  38. 38.
    Wilson WB, Perez GM, Kleinschmidt-DeMasters BK: Sudden onset of blindness in patients treated with oral CCNU and low-dose cranial irradiation. Cancer 59: 901–907, 1987Google Scholar
  39. 39.
    Ang LC, Heathcote JG, Gilbert JJ: Multifocal pontine leukoencephalopathy — a clinicopathologic study of three cases. J Neuropathol Exp Neurol 45: 350, 1986Google Scholar
  40. 40.
    Watanabe I, Hodges GR, Dworzack DL, Kepes JJ, Duensing GF: Neurotoxicity of intrathecal gentamicin: a case report and experimental study. Ann Neurol 4: 564–572, 1978Google Scholar
  41. 41.
    Vinters HV, Anders KH, Barach P: Focal pontine leukoencephalopathy in immunosuppressed patients. Arch Pathol Lab Med 111: 192–196, 1987Google Scholar
  42. 42.
    Clemente CD, Holst EA: Pathological changes in neurons, neuroglia, and blood-brain barrier induced by x-irradiation of heads of monkeys. A.M.A. Arch Neurol Psychiatry 71: 66–79, 1954Google Scholar
  43. 43.
    Kemper TL, O'Neill R, Caveness WF: Effects of single dose supervoltage whole brain radiation in Macaca mulatta. J Neuropathol Exp Neurol 36: 916–940, 1977Google Scholar
  44. 44.
    Tiller-Borcich JK, Fike JR, Phillips TL, Davis RL: Pathology of delayed radiation brain damage: an experimental canine model. Radiat Res 110: 161–172, 1987Google Scholar
  45. 45.
    Lelieveld P, Brown JM, Goffinet DR, Schoeppel SL, Scoles M: The effect of BCNU on mouse skin and spinal cord in single drug and radiation exposure. Radiat Oncol Biol Phys 5: 1565–1568, 1979Google Scholar
  46. 46.
    Smith BH, Greenwood MA, Cummins CJ, Ellis J, Gibson C, Kornblith PL: Non-nuclear cytotoxic actions of DNA cross-linking and/or alkylating agents in glioma-derived cell lines. In: Biology of brain tumor. Walker MD, Thomas DGT (eds), Martinus Nijhoff Pub., 1986Google Scholar
  47. 47.
    Layton PB, Greenberg HS, Stetson PL, Ensminger WD, Gyves JW: BCNU solubility and toxicity in the treatment of malignant astrocytomas. J Neurosurg 60: 1134–1137, 1984Google Scholar

Copyright information

© Kluwer Academic Publishers 1989

Authors and Affiliations

  • Marc K. Rosenblum
    • 1
  • Jean-Yves Delattre
    • 2
  • Russell W. Walker
    • 3
  • William R. Shapiro
    • 4
  1. 1.The Departments of Pathology (Neuropathology)Memorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.The Departments of Pathology NeurologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  3. 3.The Departments of Pathology NeurologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  4. 4.The Departments of Pathology NeurologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA

Personalised recommendations