Because of the diffuse nature of central nervous system (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 to 5 months. Until the mid 1990s, radiation therapy had been the standard treatment, with doses of up to 45 Gy using standard fractionation. A prospective trial by the Radiation Therapy Oncology Group (RTOG-8315) used 40 Gy whole-brain radiation therapy (WBRT) and a 20 Gy boost to the tumor and found that the results were no better than had been previously reported with a median survival of 1 year and 28% of the patients surviving 2 years.[1,2] Disease recurs in the brain in 92% of patients despite 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 (including RTOG-8806) used preirradiation cyclophosphamide, doxorubicin, vincristine, and dexamethasone followed by WBRT.[3,4] 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 neurologic toxic effects.[3,5,6,7,8,9,10] A retrospective review of 226 patients suggested improved results with the use of high-dose methotrexate or cytarabine with radiation therapy rather than with other combination regimens.
A multicenter trial (RTOG-9310) of 102 patients used high-dose methotrexate (2.5 g/m2) for five cycles, intravenous vincristine, oral procarbazine, intraventricular methotrexate, and either 45 Gy of WBRT or 36 Gy in a hyperfractionated schedule. Median progression-free survival (PFS) was 24 months, and median overall survival (OS) was 37 months.[Level of evidence: 3iiiA] Severe delayed neurologic toxic effects were seen in 15% of patients.
Another multicenter trial (EORTC-20962), which is now closed, was comprised of 52 patients younger than 66 years who used high-dose methotrexate, teniposide, carmustine, methylprednisolone, intrathecal methotrexate, cytarabine, and hydrocortisone followed by 40 Gy of radiation therapy; the median survival was 46 months, but a 10% toxic death rate occurred even in this younger patient population.[Level of evidence: 3iiiA] Follow-up was too short (median 27 months) to fully assess severe delayed neurologic toxic effects.