Watterson J, Toogood I, Nieder M, Morse M, Frierdich S, Lee Y, Moertel C L, Priest J R
Children's Hospital, St. Paul, MN 55105.
Cancer. 1994 Dec 1;74(11):3034-41. doi: 10.1002/1097-0142(19941201)74:11<3034::aid-cncr2820741122>3.0.co;2-o.
Intrathecal chemotherapy, radiation therapy, and systemic chemotherapy are used for both prophylaxis and treatment of central nervous system (CNS) disease in hematologic malignancies. Twenty-three cases of myelopathy that occurred in patients who received intensive CNS-directed therapy were evaluated to identify the determinants of this severe CNS toxicity.
Nine cases treated by the authors and 14 collected from the literature are discussed. Twelve had Burkitt's leukemia/lymphoma. Patient ages ranged from 3 to 30 years (median, 15 years). The dose intensity of CNS-directed therapies, including intrathecal cytosine arabinoside (ara-C), intrathecal methotrexate (MTX), systemic high dose (HD) MTX, systemic HD ara-C, systemic thiotepa, and CNS radiation, was evaluated by the determination of single drug doses and cumulative total drug or irradiation doses over elapsed treatment durations.
Central nervous system treatment was prophylactic in 10 cases; active CNS disease was being treated in 13 cases. One patient received only intrathecal ara-C before toxicity occurred; other received intrathecal ara-C and varying combinations of intrathecal MTX, HD ara-C, HD MTX, CNS radiation, and systemic thiotepa. Eight patients died of toxicity, of whom 6 had autopsy-proven cord necrosis; 3 were ventilator-dependent; 10 had persistent paraplegia or paraparesis; and 2 recovered completely.
Both highly intensive, short CNS treatment sequences and lower intensity, long term cumulative treatments may result in this rare but severe myelopathy. The cause is multifactorial, with systemic chemotherapy, intrathecal chemotherapy, and radiation therapy contributing to toxicity. Multiple intrathecal ara-C and/or MTX doses given at frequent (daily) intervals should be avoided. Concurrent intrathecal ara-C and systemic HD ara-C also appear to be especially toxic. Intrathecal hydrocortisone given with intrathecal ara-C does not protect against myelopathy. Multiple, frequently spaced courses of CNS-directed therapies must be avoided, especially in patients who have received prior CNS radiation.
鞘内化疗、放射治疗和全身化疗用于血液系统恶性肿瘤中枢神经系统（CNS）疾病的预防和治疗。对接受强化CNS定向治疗的患者中发生的23例脊髓病进行了评估，以确定这种严重CNS毒性的决定因素。
讨论了作者治疗的9例病例和从文献中收集的14例病例。12例患有伯基特白血病/淋巴瘤。患者年龄范围为3至30岁（中位数为15岁）。通过确定单药剂量以及在整个治疗期间累积的总药物或照射剂量，评估了CNS定向治疗的剂量强度，包括鞘内阿糖胞苷（ara-C）、鞘内甲氨蝶呤（MTX）、全身高剂量（HD）MTX、全身HD阿糖胞苷、全身噻替派和CNS放射治疗。
10例患者接受CNS预防性治疗；13例患者正在治疗活动性CNS疾病。1例患者在毒性发生前仅接受鞘内阿糖胞苷治疗；其他患者接受鞘内阿糖胞苷以及鞘内甲氨蝶呤、HD阿糖胞苷、HD甲氨蝶呤、CNS放射治疗和全身噻替派的不同组合治疗。8例患者死于毒性，其中6例经尸检证实有脊髓坏死；3例依赖呼吸机；10例有持续性截瘫或轻瘫；2例完全康复。
高强度、短疗程的CNS治疗方案和低强度、长期累积治疗均可能导致这种罕见但严重的脊髓病。其病因是多因素的，全身化疗、鞘内化疗和放射治疗均会导致毒性。应避免频繁（每日）间隔给予多次鞘内阿糖胞苷和/或甲氨蝶呤剂量。同时给予鞘内阿糖胞苷和全身HD阿糖胞苷似乎也具有特别的毒性。鞘内阿糖胞苷与鞘内氢化可的松联合使用并不能预防脊髓病。必须避免多次、间隔时间短的CNS定向治疗疗程，尤其是在已接受过CNS放射治疗的患者中。
