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Treatment of Neoplastic Meningitis with Intrathecal Temozolomide¹

Departments of Pathology [G. E. A., R. E. M., D. D. B., H. S. F.], Surgery (Neurosurgery) [J. H. S., G. E. A., A. H. F., H. S. F.], and Pediatrics [H. S. F.], Duke University Medical Center, Durham, North Carolina 27710 and Schering-Plough Research Institute, Kenilworth, New Jersey 07033 [W. R. B.]

Neoplastic meningitis (NM) results from leptomeningeal dissemination of cancers arising within the central nervous system or metastasizing to the leptomeninges from systemic neoplasms. The inability to produce therapeutic drug levels intrathecally (IT) with systemic administration and the minimal efficacy of chemotherapeutic agents currently available for direct IT use limit therapy.

Temozolomide [8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4([³H])-one] is a novel methylating agent with proven activity against intraparenchymal malignant gliomas (MGs). Insolubility of the standard formulation prevents its efficacious use as an IT agent, however. To overcome this obstacle, we have developed a unique microcrystalline formulation of temozolomide with greatly enhanced solubility. Treatment of athymic rats bearing subarachnoid MER- human MG xenografts with four doses of IT microcrystalline temozolomide over a 2-week period produced a 142% increase in median survival at individual doses of 2.2 µmol (P = 0.0073) and a >367% increase in median survival at individual doses of 6.8 µmol (P = 0.0015). At the higher dose tested, three of eight rats treated developed no neurological symptoms and had no evidence of residual tumor on histological examination after treatment. Use of this microcrystalline formulation in athymic rats bearing subarachnoid MER+ human MG xenografts increased median survival >132% (P < 0.0058) at both dose levels tested. Toxicity directly attributable to the IT administration of microcrystalline temozolomide was exhibited in the highest dose groups only and was limited to small patchy areas of focal demyelination involving <5% of spinal cord long tracks.

These results suggest that a dose range for both toxicity and activity has been defined for IT microcrystalline temozolomide in the treatment of NM in athymic rats, and a Phase I trial for the treatment of patients with NM using IT microcrystalline temozolomide should now be undertaken.

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