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Adding high-dose methotrexate to whole-brain radiotherapy improves survival in primary central nervous system lymphoma. However, the high neurotoxicity rates observed, especially in the elderly, raised interest in exploring other alternatives such as reduced-dose radiotherapy and chemotherapy-only treatments.Phase II studies suggested that omitting radiotherapy decreases progression-free survival (PFS) but not overall survival. A randomized phase III trial testing chemotherapy with/without radiation found similar results. However, interpretation of that trial has been difficult because of the chemotherapy regimen used (methotrexate with/without ifosfamide), intrinsic methodological problems and lack of neuropsychological evaluation. It also remains unclear whether chemotherapy-only treatments could ultimately result in worse cognitive outcomes in comparison with combined chemotherapy and radiotherapy because the higher rates of relapses could result in additional neurotoxicity from salvage treatments and brain damage by relapsing tumor. Given differences in relapses and neurotoxicity rates according to age, it is also unclear how results apply to younger versus older patients.Given the lack of better data, omitting radiotherapy currently seems a justifiable choice in routine practice, particularly in the elderly, but the question remains unsettled. Ongoing studies are investigating other consolidation options, including reduced-dose radiotherapy and high-dose chemotherapy with stem-cell rescue, aiming at improving disease control and decreasing neurotoxicity.