Treatment of neoplastic meningitis with intrathecal temozolomide

Neoplastic meningitis (NM) results from leptomeningeal dissemination of can cers arising within the central nervous system or metastasizing to the lept omeninges from systemic neoplasms. The inability to produce therapeutic dru g levels intrathecally (IT) with systemic administration and the minimal ef ficacy of chemotherapeutic agents currently available for direct IT use lim it therapy. Temozolomide [8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4([H-3])- one] is a novel methylating agent with proven activity against intraparench ymal malignant gliomas (MGs), Insolubility of the standard formulation prev ents its efficacious use as an IT agent, however. To overcome this obstacle , we have developed a unique microcrystalline formulation of temozolomide w ith greatly enhanced solubility, Treatment of athymic rats bearing subarach noid MER- human MG xenografts with four doses of IT microcrystalline temozo lomide over a 2-week period produced a 142% increase in median survival at individual doses of 2.2 mu mol (P = 0.0073) and a >367% increase in median survival at individual doses of 6.8 mu mol (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 treatm ent. Use of this microcrystalline formulation in athymic rats bearing subar achnoid MER+ human MG xenografts increased median survival >132% (P < 0.005 8) at both dose levels tested. Toxicity directly attributable to the IT adm inistration of microcrystalline temozolomide was exhibited in the highest d ose groups only and was limited to small patchy areas of focal demyelinatio n 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 us ing IT microcrystalline temozolomide should now be undertaken.