Therapeutic management of primary central nervous system lymphoma: lessons from prospective trials

Primary central nervous system lymphomas (PCNSL) are aggressive malignancies, exhibiting one of the worst prognoses among lymphomas. The best treatment modality for PCNSL has not yet been identified. Several therapeutic questions still remain unanswered, and some methodological pitfalls in clinical trials prevent definitive conclusions from being drawn. In this review, certain aspects of trial design as well as emerging therapeutic guidelines are analyzed, and future perspectives are discussed. In the vast majority of prospective trials, general criteria for treatment of aggressive lymphomas were adopted, choosing primary chemotherapy (CHT) followed by radiotherapy (RT) as therapeutic modality. This strategy produced a five-year survival of 22%- 40% in comparison to the 3%-26% reported with RT alone. Systemic high-dose methotrexate (HD-MTX) seems to be the most effective drug, producing a response rate of 80%-90% and a two-year survival of 60%-65%. To date, the addition of other drugs at conventional doses have not consistently improved outcome. With a few exceptions, any regimen without HD-MTX comprehensively performed no better than RT alone. In combined treatment. RT doses should be decided on the bases of response to primary CHT and the number of lesions, and, until definitive conclusions from well-designed trials are available, RT parameters should follow the widely accepted principles used for other aggressive lymphomas. CHT as exclusive treatment, keeping RT for relapses or persistent disease, appears to be an attractive strategy. However, the worldwide experience with this modality is still limited, and corroborating data are needed. Intrathecal CHT still has not found a defined role in PCNSL management. Preliminary data seem to indicate that adequate meningeal treatment with HD-MTX, but without intrathecal CHT, could also be suitable in positive-cerebrospinal fluid patients. Future efforts should be addressed to identify new active drugs and more efficient CHT combinations, to evaluate the efficacy of high-dose CHT supported by autologous peripheral blood stem cells transplantation, and to clarify the impact of RT delay in complete responders, the usefulness of intrathecal CHT, and the best management for elderly patients. The assessment of impact of treatment on neuropsychological functions and quality of life is a mandatory endpoint in clinical trials.