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.