EXCESSIVE SPINAL-CORD TOXICITY FROM INTENSIVE CENTRAL-NERVOUS-SYSTEM DIRECTED THERAPIES

Background. Intrathecal chemotherapy, radiation therapy, and systemic chemotherapy are used for both prophylaxis and treatment of central ne rvous system (CNS) disease in hematologic malignancies. Twenty-three c ases of myelopathy that occurred in patients who received intensive CN S-directed therapy were evaluated to identify the determinants of this severe CNS toxicity. Methods. Nine cases treated by the authors and 1 4 collected from the literature are discussed. Twelve had Burkitt's le ukemia/lymphoma. Patient ages ranged from 3 to 30 years (median, 15 ye ars). The dose intensity of CNS-directed therapies, including intrathe cal cytosine arabinoside (ara-C), intrathecal methotrexate (MTX), syst emic high dose (HD) MTX, systemic HD ara-C, systemic thiotepa, and CNS radiation, was evaluated by the determination of single drug doses an d cumulative total drug or irradiation doses over elapsed treatment du rations.Results. Central nervous system treatment was prophylactic in 10 cases; active CNS disease was being treated in 13 cases. One patien t received only intrathecal ara-C before toxicity occurred; others rec eived intrathecal ara-C and varying combinations of intrathecal MTX, H D ara-C, HD MTX, CNS radiation, and systemic thiotepa. Eight patients died of toxicity, of whom 6 had autopsy-proven cord necrosis; 3 were v entilator-dependent; 10 had persistent paraplegia or paraparesis; and 2 recovered completely. Conclusion. Both highly intensive, short CNS t reatment sequences and lower intensity, long term cumulative treatment s may result in this rare but severe myelopathy. The cause is multifac torial, with systemic chemotherapy, intrathecal chemotherapy, and radi ation therapy contributing to toxicity. Multiple intrathecal ara-C and /or MTX doses given at frequent (daily) intervals should be avoided. C oncurrent intrathecal ara-C and systemic HD ara-C also appear to be es pecially toxic. Intrathecal hydrocortisone given with intrathecal ara- C does not protect against myelopathy. Multiple, frequently spaced cou rses of CNS-directed therapies must be avoided, especially in patients who have received prior CNS radiation.