Leptomeningeal metastases: Rationale for systemic chemotherapy or what is the role of intra-CSF-chemotherapy?

Malignant subarachnoid deposits complicate both primary central nervous system (CNS) tumors and systemic neoplasms. Although the pathophysiology of symptoms and signs can not be separated by the category of primary tumors that seeds the leptomeninges, the approach to therapy is not similar in primary CNS tumors and in systemic neoplasms. Standard therapy for subarachnoid seeding in primary CNS tumors include conventional or high doses of systemic chemotherapy with various combinations of radiotherapy given either to limited fields or to the whole neuroaxis. Direct administration of chemotherapy to the CSF is not being used. In contrast, whenever a systemic tumor seeds the subarachnoid space the standard approach includes intensive intra-CSF chemotherapy, radiotherapy to limited or extended CNS fields and various combinations of systemic chemotherapy. The published experience with the conventional therapy is reviewed and is critically analyzed. Evidence indicating that high dose systemic chemotherapy can replace intra-CSF treatment in some subgroups are also reviewed and the rationale for this approach is specified. Recent experience in which intra-CSF therapy was prospectively eliminated from the treatment protocol of leptomeningeal metastases of solid tumors reveals that the response rate and survival are similar to those obtained by protocols that differed only by the inclusion of intra-CSF chemotherapy. Patients who were treated by radiotherapy alone combined with systemic chemotherapy but without the intra-CSF therapy were spared the high rate of early and delayed complications directly related to intra-CSF therapy. Still, treatment outcome did not differ. Therefore, future research efforts and prospective clinical trials should investigate the best chemotherapeutic schedules and their sequencing with radiotherapy or with more intensive complementary systemic chemotherapy schemes. Newly designed drugs with long circulation time and improved CNS penetration may serve for this purpose.