Anaplastic gliomas and recurrent medulloblastomas continue to be refractory to most forms of therapy. We have organized a multi- institution clinical consortium (Duke, University of Alabama at Birmingham, Evanston Hospital of Northwestern University, and the University of Western Ontario) to test therapeutic hypotheses by conducting clinical trials of therapy for patients with primary central nervous system (CNS) neoplasms. We are proposing to conduct 3 new trials (a phase III adjuvant and 2 phase II recurrent disease trials) and to continue 3 on-going clinical protocols. The hypotheses to be tested are: (1) There is a significant hypoxic fraction of cells in anaplastic gliomas that is relatively resistant to radiotherapy but that is sensitive to bioreductive alkylating agents, such as mitomycin C. This will be tested in a phase III trial in which patients who receive mitomycin C during radiotherapy will be compared to those receiving no cytotoxic drugs during radiation; (2) The therapeutic effect of nitrosoureas can be potentiated by thiopurines. This will be tested in the same phase III trial in which patients will be randomly assigned to receive either BCNU alone or BCNU + 6-mercaptopurine following completion of radiotherapy; (3) Alpha-interferon will act synergistically with active alkylating drugs in patients with recurrent anaplastic gliomas. This will be tested in concurrent phase II trials of either CCNU (in patient not previously treated with nitrosoureas) or cyclophosphamide (in patients previously treated with nitrosoureas) with or without alpha-interferon in patients with recurrent primary CNS tumors; (4) Treatment of previously untreated primary CNS tumors will produce a higher response rate than treatment of tumors that have failed other forms of therapy. This will be tested in a continuing study of intracarotid cisplatin in patients with newly diagnosed anaplastic cerebral glioma; and (5) Pre-clinical and pilot studies of melphalan activity will be confirmed in clinical trials. This will be tested in continuing phase II studies of intravenous melphalan in patients with recurrent oligo-dendroglioma or medulloblastoma. Central neuropathology, neuroradiology, radiation oncology, and data management committees monitor quality control of all protocols. Total accrual is anticipated to be approximately 200 patients per year. Concomitant studies of karyotype and oncogene expression, DNA repair capacity, and metabolic imaging (including positron emission tomography and magnetic resonance spectroscopy) will solidify the clinical data base and allow identification of important new prognostic factors.
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