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Purpose: To assess the efficacy and toxicity of chemotherapy alone in patients older than 60 years with primary CNS lymphoma., Patients and Methods: Fifty patients with a median age of 72 years and a median Karnofsky performance score (KPS) of 50 were eligible for this multicenter phase II study. The protocol consisted of high-dose methotrexate (MTX), lomustine, procarbazine, methylprednisolone, and intrathecal chemotherapy with MTX and cytarabine. The patients received one induction cycle; if objective response was achieved, five additional maintenance cycles were administered every 6 weeks. The median follow-up of patients was 3 years., Results: Twenty four patients (48%) achieved an objective response (compete response [CR], 42%; partial response, 6%), with a median duration of CR of 27 months (range, 3 to 47+ months). Overall median survival time was 14.3 months, and 1-year progression-free survival was 40% (95% confidence interval [CI], 26% to 53%). Myelosuppression was the most frequent side effect, with grade 3 to 4 neutropenia in 19% of patients. One patient died during chemotherapy, as a result of pulmonary embolism. Most patients improved or preserved their cognitive functions (47% and 45% of the patients, respectively) and KPS (36% and 52% of the patients, respectively) until relapse, whereas cognitive and KPS decline attributed to delayed treatment neurotoxicity occurred in 8% and 12% patients, respectively., Conclusion: In the elderly, this chemotherapy regimen compares favorably with radiotherapy (RT) alone and reduces considerably the risk of delayed neurotoxicity associated with combined chemoradiotherapy. Chemotherapy alone is an appropriate strategy in older patients to delay or avoid RT.