ALIGNANT gliomas have a high rate of local recur- rence; 22 therefore, to treat these tumors, we developed a novel means to deliver chemothera- peutic agents via biodegradable sustained-release poly- mers. 5 This local drug-delivery system provides sustained high drug levels in brain tissue. 19,33,36 We had previously evaluated 1,3-bis(2-chloroethyl)-1- nitrosourea (BCNU), delivered via polymers, in the labo- ratory and clinic as a treatment for brain tumors. The agent BCNU, a low-molecular-weight, lipid-soluble nitro- sourea, was chosen because of its demonstrated efficacy in animals 29,32 and its well-studied clinical usage. 5,26,34,35 Rats with intracranial 9L gliosarcoma treated with BCNU in polymer demonstrated a cure rate of up to 47% com- pared to a 0% cure rate in rats treated with systemic BCNU. 32 A Phase I–II study in humans, using BCNU in polymer to treat recurrent malignant gliomas, showed that these patients had an average survival of 48 weeks following reoperation and placement of the polymer containing BCNU. 5 This finding compares favorably to studies of individuals following reoperation for recurrent malignant gliomas in which the median survival is 36 weeks. 3,21 Phase III placebo-controlled studies have demonstrated a similar prolongation in survival. The promise of this approach is apparent in its ability to deliver agents that otherwise could not adequately cross the blood-brain barrier. Cyclophosphamide, a water-solu- ble chemotherapeutic agent, has been used widely outside the central nervous system (CNS), but its value for CNS tumors is limited because of the toxicity of the large doses required to achieve adequate CNS levels when the drug is J. Neurosurg. / Volume 82 / March, 1995 J Neurosurg 82:481–486, 1995 Effectiveness of controlled release of a cyclophosphamide derivative with polymers against rat gliomas KEVIN D. JUDY , M.D., ALESSANDRO OLIVI, M.D., KWAME G. BUAHIN, M.D., PH.D., ABRAHAM DOMB, PH.D., JONATHAN I. EPSTEIN, M.D., O. MICHAEL COLVIN, M.D., AND HENRY BREM, M.D. Departments of Neurosurgery, Oncology, and Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland; and The Hebrew University School of Pharmacy, Jerusalem, Israel  Most malignant gliomas grow despite treatment by standard chemotherapeutic agents. The authors explored the use of an innovative drug, 4-hydroperoxycyclophosphamide (4HC), delivered via a controlled-release biodegradable poly- mer to determine whether local delivery would enhance efficacy. This drug is an alkylator-type chemotherapeutic agent derived from cyclophosphamide. Unlike the parent drug, which requires activation by hepatic microsomes, 4HC is active in vitro. Two rat glioma cell lines, 9L and F98, were treated in cell culture with medium containing 4HC. Both cell lines were more sensitive to 4HC than to a nitrosourea, BCNU, an agent of established value in the local therapy of gliomas. Ninety Fischer 344 rats implanted with 9L or F98 gliomas were treated with an intracranial polymer implant con- taining 0% to 50% loaded 4HC in the polymer, and it was found that 20% 4HC–loaded polymers caused minimum local brain toxicity and maximum survival. These polymers were then used to compare the in vivo efficacy of 4HC to BCNU in rats implanted with 9L glioma. Animals with brain tumors treated with 4HC had a median survival span of 77 days compared to the median survival of 21 days in BCNU-treated animals and median survival of 14 days in untreated animals. Long-term survival for more than 80 days was 40% in the 4HC-treated rats versus 30% in the BCNU-treated rats. The polymer carrier used in this study was a copolyanhydride of dimer erucic acid and sebacic acid 1:1, which was able to maintain the hydrolytically unstable 4HC in a stable state for local delivery. Thus, it is concluded that 4HC- impregnated polymers provide an effective and safe local treatment for rat glioma. KEY WORDS • chemotherapy • brain neoplasm • glioma • 4HC • drug delivery • biodegradable polymer M 481