Intrathecal chemotherapy for hematologic malignancies: drugs and toxicities

Intrathecal (IT) chemotherapy is an important component of the prophylaxis or treatment of hematologic malignancies in the central nervous system (CNS), especially in patients with acute lymphoblastic leukemia and aggressive lymphomas. Different regimens of IT chemotherapies have been formulated, often in conjunction with systemic high-dose chemotherapy leading to penetration of the drugs into the cerebrospinal fluid (CSF). The three commonest IT drugs are methotrexate, cytosine arabinoside (Ara-C), and corticosteroids. The CSF half-lives of methotrexate and Ara-C are much prolonged, a factor to be considered if these drugs are also administered systemically in high doses. Neurotoxicities attributed to IT chemotherapy have been reported, including spinal cord lesions, seizures, and encephalopathy. Spinal cord lesions, manifesting as tetraplegia, paraplegia, and cauda equina syndrome, are the commonest neurotoxicity. It is mostly related to combined IT methotrexate and Ara-C, or Ara-C as the sole IT agent when given at high doses or as a slow-release preparation. Cord lesions rarely recover and patients are left with motor deficits, bowel and urinary disabilities. Seizures and encephalopathy are reported in relatively fewer patients, with variable manifestations and prognosis. Knowledge of the pharmacokinetics, dosing schedules and potential toxicities of IT chemotherapeutic drugs is important in the design of CNS prophylaxis and treatment in hematologic malignancies.