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The most notable risk factor for the development of primary central nervous system lymphoma (PCNSL) is immunodeficiency. PCNSL was historically treated with cranial irradiation, i.e., whole-brain radiotherapy (WBRT). WBRT may become complicated by the development of chronic and late neurotoxicity. In order to avoid these complications, treatment with chemotherapy alone was suggested. The optimal management of PCNSL is poorly demarcated. The use of wide variety of methotrexate (MTX) based treatment regimens resulted in excellent survival rates. However, disease control with these regimens is unpredictable. PCNSL is a diffuse disease, partial or complete surgical removal provides minimal benefit for the patient with a median survival of 1-5 months with surgery alone.
Radiation therapy up to 45Gy has been considered as the standard treatment till mid-1990s. A prospective trial performed by the Radiation Therapy Oncology Group (RTOG -8315) treated patients with a 40 Gy WBRT and 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 the patients survived 2 years. Despite high radiation doses used, brain recurrence occurred in 92% of patients. Although more than 50% of patients achieved an initial complete response after WBRT, recurrences were frequent and the overall survival was only 12-18 months. In the late 1970s, treatment strategies for PCNSL started to change. A study by Ervin and Canellos demonstrated the remarkable efficacy of high dose MTX plus leucovorin in the treatment of recurrent CNS lymphomas.
It is now recognized that a large-cell lymphoma within the brain microenvironment has, for unclear biological reasons, an approximately twofold sensitivity to high-dose MTX as compared to systemic lymphomas of the same histology. A pilot study conducted at the Centre Léon Bérard (Lyon, France) from 1984 to 1993 tested the C5R protocol derived from chemotherapy regimens, used for pediatric Burkitt lymphomas: four polychemotherapy courses with HD-MTX and cytarabine, followed by brain radiotherapy. The study reported a 56% complete response (CR) and 56% 5-year OS, but induced high toxicity in patients over 60 years of age. That is attributed to the fact that the median age of PCNSL patients is approximately 56 years in most series, as well as to age-related treatment-induced neurotoxicity likely being a continuous variable. It has been established that a very large proportion of PCNSL patients are at high risk for clinically significant delayed radiation injury from standard-dose whole-brain irradiation. For this reason, a reduction approach has been applied in parallel to maximize the potential efficacy of repeat cycles of high-dose MTX as a monotherapy without consolidative brain irradiation. In some clinical series, this approach appeared to yield rates of long-term survival that are comparable with that achieved with combined modality therapy.
Given that the incidence of PCNSL is increasing in patients over 65 years old (the group most vulnerable to treatment-related toxicities), high-dose MTX monotherapy, which is generally well-tolerated, has been prescribed for many years with significant efficacy both on induction and at relapse in older patients. Moreover, an important randomized controlled trial carried out by Thiel et al demonstrated that the omission of standard dose, WBRT as consolidation after the MTX-based induction of chemotherapy had no effect on OS. PCNSL was considered rare; thus, the optimum management of patients with this disease remains to be established. The increased incidence of PCNSL and the recognition that radiotherapy often produced a dramatic response associated with rapid relapse have led to the continued investigation of improved therapies for PCNSL over the past 20 years. The mortality associated with delayed neurotoxicity in patients receiving both chemotherapy and WBRT has led to comparable survival rates, irrespective of whether WBRT is used or not.
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