Flowchart of therapeutic management of HIV-negative patients with PCNSL. ¹Other clinical and biochemical parameters may be considered. An overall evaluation of an experienced multidisciplinary team is recommended. ²An undebatable cutoff to define “elderly” population does not exist. Age should not be used as an exclusive parameter to define therapeutic approach. Age, comorbidity, and ASCT feasibility should be considered together to define treatment. ³Several chemotherapy regimens for young patients are available; some examples are reported in parenthesis. The MATRix regimen is supported by the highest level of evidence as assessed in an international randomized trial. ⁴Several chemotherapy regimens for elderly patients are available; some examples are reported in parenthesis. The PRIMAIN regimen has been assessed in the largest single-arm phase 2 trial; MPV and MT have been addressed in a randomized trial performed in the pre-rituximab era. The effect of the addition of this antibody both on toxicity and efficacy remains to be assessed. ⁵Randomized trials suggest both WBRT and ASCT are effective as consolidation therapies in young patients, with a higher risk of neurotoxicity after WBRT. The discussion with selected patients about the pros and cons of the use of consolidation WBRT or ASCT is recommended. ⁶Randomized trials focused on consolidation therapies in elderly patients are not available. All consolidation options are supported by single-arm phase 2 trials. ⁷Radiation field and dose should be chosen on the basis of response to primary chemotherapy. WBRT dose reduction to 23.4 Gy is recommended in patients who achieved a complete remission after induction of chemoimmunotherapy. ⁸Encouraging data with maintenance with temozolomide or procarbazine are available. Lenalidomide maintenance seems to be an interesting experimental option. ⁹Watchful waiting is suggested only in patients in complete remission after well-documented induction chemoimmunotherapy. ASCT, myeloablative chemotherapy supported by ASCT; HD-ARAC, high-dose cytarabine; HD-MTX, high-dose methotrexate; LVEF, left ventricular ejection fraction; MPV, HD-MTX/procarbazine/vincristine; MT, HD-MTX/temozolomide; MT-R, rituximab/HD-MTX/temozolomide; NYHA, New York Hospital Association; PRIMAIN, rituximab/HD-MTX/procarbazine; R-MBVP, rituximab/HD-MTX/carmustine/etoposide/HD-ARAC; R-MPV, rituximab/HD-MTX/procarbazine/vincristine.