The treatment of this disease is controversial as noted by the NCI: "Because of the diffuse nature of CNS lymphomas, aggressive surgical decompression with partial or gross total removal of the tumor is of no benefit to the patient. Median survival with surgery alone is in the range of only 1-5 months. Until recently, radiation therapy has been the standard treatment, with doses of up to 45 Gy using standard fractionation. When the Radiation Therapy Oncology Group used 40 Gy whole-brain irradiation and a 20 Gy boost to the tumor, the results were no better than had been previously reported, with median survival of 1 year and 28% surviving 2 years. Disease recurs in the brain in 92% of patients despite the high doses of radiation. The addition of spinal axis radiation does not affect survival because it does not prevent cerebral relapse.

Two multicenter prospective trials used pre-irradiation cyclophosphamide, doxorubicin, vincristine, and dexamethasone followed by whole-brain irradiation. Median survival times were no better than for radiation therapy alone. The failure of these and other combined modality trials  has been attributed to poor penetration of standard drugs through the blood- brain barrier and to increased neurotoxicity.A retrospective review of 226 patients suggested improved results using high-dose methotrexate or cytarabine with radiation therapy over other combination regimens.