Primary Central Nervous System Lymphoma

The most notable risk factor for the development of primary central nervous system lymphoma (PCNSL) is immunodeficiency [1-7]. 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 [8]. 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 [9] demonstrated the remarkable efficacy of high dose MTX plus leucovorin in the treatment of recurrent CNS lymphomas.

Large-cell lymphoma within the brain has an average of twofold sensitivity to the high dose MTX compared to the systemic lymphomas of the same histology [10]. A study performed in France from 1984 to 1993 tried the CR5 protocol which is a chemotherapy regimen used for the treatment of pediatric Burkett lymphomas. The regimen involved four polychemotherapy courses with high dose MTX and cytarabine followed by brain radiation. The complete response was 56% and the 5-years overall survival was 56%. However, high toxicity rate was reported in patients over 60 years of age [11]. 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 the majority of PCNSL patients will experience a significant delayed radiation injury from standard WBRT. In an attempt to avoid such toxicity, a reduction approach has been applied aiming to maximize the efficacy of repeat cycles of high dose MTX as a monotherapy. This approach has proven long-term survival rates similar to that achieved with combined modality treatment.

The incidence of PCNSL is increasing in patient population >65 years old. This group is most vulnerable to the delayed radiation toxicity. Hence, 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] proved that the overall survival was not affected after omitting the standard dose WBRT as a consolidation therapy after MTX induction.

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[17,18].