The treatment of PCNSL differs from that of systemic NHL because chemotherapeutic agents need to cross the BBB in PCNSL. Inadequate drug delivery to the tumor is the main factor underlying unsatisfactory responses in patients with PCNSL, and this prevents the use of standard treatments for NHL, such as CHOP-like chemotherapy containing an anthracycline. The lymphoma itself does not appear to be specifically resistant. Because many drugs are substrates for transporter molecules such as P-glycoprotein, multidrug-resistance-associated protein, and organic anion-transporting polypeptides, several candidate drugs are substrates or inhibitors of these carrier proteins. Preclinical studies are ongoing. Future leads include lipid-soluble analogs or prodrugs that are not substrates for the barrier efflux system. Novel approaches with proven feasibility are currently limited to high-dose chemotherapy with hematopoietic rescue and BBB disruption that possibly circumvent the hurdle represented by the BBB. The possible benefit of adding rituximab to first-line treatment remains to be demonstrated in the specific setting of PCNSL. Neurotoxicity also must be better controlled, possibly by using compounds that protect the brain without undermining treatment efficacy.
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