The most important risk factor for the development of primary central nervous system lymphoma (PCNSL) is immunodeficiency [1-7]. PCNSL has historically been treated with cranial irradiation, i.e., whole brain radiation therapy (WBRT). WBRT can become complicated due to the development of chronic and late neurotoxicity. To avoid these complications, treatment with chemotherapy alone has been suggested. The optimal management of PCNSL is poorly demarcated. The use of a wide variety of methotrexate (MTX) treatment regimens has resulted in excellent survival rates. However, disease control with these regimens is unpredictable. PCNSL is a widespread disease, partial or complete surgical removal provides minimal benefit to the patient with an average survival of 1-5 months with surgery alone. Say no to plagiarism. Get a tailor-made essay on "Why Violent Video Games Shouldn't Be Banned"? Get an original essay Radiation therapy of up to 45 Gy was considered the standard treatment until the mid-1990s. A prospective study performed by the Radiation Therapy Oncology Group (RTOG -8315) treated patients with a WBRT of 40 Gy and a 20 Gy boost to the gross tumor demonstrated similar results to previously reported studies. The study showed a median survival of 1 year and 28% of patients survived 2 years [8]. Despite the high doses of radiation used, brain recurrence occurred in 92% of patients. Although more than 50% of patients achieved an initial complete response after WBRT, relapses were frequent and overall survival was only 12–18 months. In the late 1970s, treatment strategies for PCNSL began to change. A study by Ervin and Canellos [9] demonstrated the remarkable efficacy of high-dose MTX plus leucovorin in the treatment of recurrent central nervous system lymphomas. Large cell lymphoma in the brain has twice the average sensitivity to high dose MTX compared to systemic lymphomas of the same histology [10]. A study conducted in France from 1984 to 1993 tested the CR5 protocol, a chemotherapy regimen used to treat pediatric Burkett lymphomas. The regimen involved four cycles of polychemotherapy with high doses of MTX and cytarabine followed by brain radiation. Complete response was 56% and 5-year overall survival was 56%. However, a high rate of toxicity has been reported in patients older than 60 years [11]. This is attributed to the fact that the average age of PCNSL patients is approximately 56 years in most cases, as well as the fact that age-related treatment-induced neurotoxicity is likely a continuous variable. It has been determined that most patients with PCNSL will experience significant delayed radiation injury resulting from standard WBRT. In an attempt to avoid such toxicity, a taper approach aimed at maximizing the efficacy of repeated courses of high-dose MTX as monotherapy was applied. This approach has demonstrated long-term survival rates similar to those achieved with combined modality treatment. The incidence of PCNSL is increasing in the population of patients older than 65 years. This group is the most vulnerable to delayed radiation toxicity. Therefore, high-dose MTX monotherapy has been used for many years for induction and relapse with significant efficacy [10, 12–15]. Furthermore, a randomized control trial by Thiel et al [16] demonstrated that overall survival was not affected after omitting standard dose WBRT as consolidation therapy after MTX induction. Please note: this is just one[17,18].