Primary CNS lymphoma (PCNSL) is a rare and aggressive brain tumor with an unsatisfactory outcome. Therapeutic progress in this field is strongly conditioned by the limited biology and the molecular knowledge about this disease, which hamperizes the identification of new targeted therapies and the poor clinical conditions and performance status of patients, rendering very difficult their enrollment in prospective trials. Chemoradiation therapy is the most commonly used strategy for patients with PCNSL, which is associated with better efficacy rates, but also with high incidence of severe neurotoxicity. As a consequence, a dilemma in PCNSL treatment is the choice between strategies designed to intensify therapy to improve the cure rate, versus strategies of treatment de-escalation to avoid severe neurotoxicity. The efficacy of chemotherapy is strongly limited by the special functional and microenvironmental characteristics of the CNS, which is variably protected by the blood-brain barrier (BBB) and includes extensive chemotherapy sanctuaries where tumor cells grow undisturbed. Drugs exhibiting a good capability to cross the BBB and drugs that can be safely administered at high doses to obtain therapeutic concentrations in the CNS are the most commonly used in the treatment of PCNSL. Consolidation after chemotherapy represents the best role for radiotherapy. Since this tumor has an infiltrative nature, the whole brain should be irradiated, with increased risk of severe neurotoxicity. Some authorities are investigating in randomized trials the impact on outcome and neurotolerability of replacing consolidation radiotherapy with other strategies, like high dose chemotherapy supported by autologous stem cell transplantation. The rationale for the use of this strategy is the administration of high doses of cytostatics to achieve therapeutic concentrations in sanctuaries, CNS organs and lymphoma tissues and to overcome drug resistance mechanisms. Future therapeutic progresses in PCNSL will be based on the expansion of molecular and biological knowledge, the improvement of therapeutic efficacy and the prevention of iatrogenic neurotoxicity.
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