Six 14-day cycles of high-dose MTX will be given at the beginning of the study. Randomization will be performed centrally at the study headquarters in UKBF Berlin already at study inclusion. Patients meeting all inclusion criteria will receive the first systemic treatment with 4 g/m2 MTX i.v. over 4 hours within 14 days. Dexamethasone in a dose of 3 x 8 mg/day orally for 10 days will additionally be given in the first cycle. This dexamethasone dose will be started 3 days before the first MTX application. Ten to 14 days after the 3rd and 6th MTX dose, the response to MTX therapy will be evaluated by MRI and a repeated CSF examination in the case of renewed CSF involvement. Assessment can also be made at any other time point if there is clinical deterioration. In all cases, the neuroradiological reference center (Department of Neuroradiology, University of Tübingen) will decide about the response to MTX therapy. MRI and CT scans should be sent to the neuroradiological reference center after HD MTX is terminated for central response evaluation. If complete remission is achieved after completing high-dose MTX therapy, patients will be treated with WBI (45 Gy in 1.5 Gy fractions) starting a minimum of 4 and a maximum of 7 weeks after the end of chemotherapy (arm A1) or WBI at first recurrence (arm A2). If primary therapy is not successful (partial remission, stable disease after the 6th cycle, progression at any time of MTX therapy), patients will receive WBI (45 Gy in 1.5 Gy fractions; arm B1) or high-dose AraC chemotherapy 3 g/m2 i.v. over 3 hours every 12 hours for 2 days (arm B2) according to the randomization. If high-dose MTX therapy leads to termination before the application of 6 cycles of MTX (see termination criteria) but allows further AraC therapy or WBI, further treatment is given in the non-CR arm according to the randomization. High-dose AraC therapy will be administered in four 3-week cycles. If complete remission occurs already after one or two cycles, only one additional cycle will be applied. Patients will not be crossed over into the B arms.

If there is a recurrence or progression after finishing a complete treatment arm, the patient can be treated with chemotherapy according to PCV protocol or WBI in the B2 arm. This decision is left up to the individual study center.

The G-PCNSL-SG-1 study is a prospective, controlled phase IV study with central randomization. Patients in both arms will be submitted to stratified randomization according to age (\< 60; \> 60) and center to minimize the effect of important therapy-related prognostic factors. The study is not blinded. Randomization will be performed centrally at study inclusion at the Institute of Medical Informatics, Biometry and Epidemiology, University Hospital Benjamin Franklin of the Free University of Berlin.

The planned study duration is 7 years - 4 years in the recruitment phase with a subsequent 3-year follow-up period and a 6-month evaluation phase. For an individual patient, the treatment time in arm A1 is 12 weeks for 6 cycles of MTX therapy, followed by a 4-7-week resting period and then 6 weeks until the completion of WBI (arm A1). In arm A2, the patient is irradiated (a total of 6 weeks) only in the case of recurrence. Up to that point, the patient will be followed up in fixed intervals like those patients in A1 after WBI. In arm B, MTX therapy is immediately followed by 6 weeks of WBI (arm B1) or the maximal 3 months of AraC therapy. After completing the protocol of the planned therapy, all patients will be followed-up for at least three years.