High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial
High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial
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DOI：
10.1016/s1470-2045(10)70229-1
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发表时间：
2010-11-01
期刊：
影响因子：
51.1
通讯作者：
Weller, Michael
中科院分区：
文献类型：
--
作者：
Thiel, Eckhard;Korfel, Agnieszka;Weller, Michael
背景大剂量甲氨蝶呤是新诊断的原发性中枢神经系统淋巴瘤患者的标准治疗。全脑放疗的作用是有争议的，因为延迟的神经毒性限制了其作为标准治疗的接受。我们的目的是调查是否一线化疗的基础上，高剂量甲氨蝶呤是非劣效于相同的化疗方案，其次是全脑放疗的总survival.Methods免疫功能正常的患者与新诊断的原发性中枢神经系统淋巴瘤从75个中心，2000年5月和2009年5月之间进行治疗。患者通过计算机生成的区组随机分配接受基于高剂量甲氨蝶呤的一线化疗，伴或不伴后续全脑放疗，并按年龄（≥ 60岁）和研究机构（柏林vs图宾根vs所有其他研究中心）分层。生物统计中心将患者分配至治疗组，并通过传真通知当地中心;分配后，医生和患者对治疗组不设盲。2000年5月至2006年8月期间入组的患者在6个14天周期的第1天接受高剂量甲氨蝶呤（4 g/m2）;此后，患者在6个14天周期的第3-5天接受高剂量甲氨蝶呤+异环磷酰胺（1.5 g/m2）。在那些被分配接受一线化疗后放疗的患者中，给予全脑放疗，总剂量为45戈伊，在工作日每天给予30次1.5戈伊。分配至一线化疗但未实现完全缓解的患者接受大剂量阿糖胞苷治疗，但未进行全脑放疗。主要终点是总生存期，分析符合方案。我们的假设是，全脑放疗的省略不会影响总生存率，非劣效性界值为0.9。该试验注册于ClinicalTrials.gov，编号NCT 00153530。结果551例患者（中位年龄63岁，IQR 55-69）入组并随机分配，其中318例按照方案接受治疗。在符合方案人群中，接受全脑放疗的患者（n=154）的中位总生存期为32.4个月（95% CI 25.8-39.0），未接受全脑放疗的患者（n= 164）为37.1个月（27.5-46.7），风险比1.06（95% CI 0.80-1.40; p=0.71）。因此，我们的主要假设没有得到证实。接受全脑放疗的患者的中位无进展生存期为18.3个月（95% CI 11.6-25.0），未接受全脑放疗的患者为11.9个月（7.3-16.5; p=0.14）。持续完全缓解患者的治疗相关神经毒性在接受全脑放疗的患者中更为常见（22/45，49%通过临床评估; 35/49，71%通过神经放射学）（9/34，26%; 16/35,46%）。解释当第一次全脑放疗被省略时，总生存率没有显著差异。线化疗新诊断的原发性中枢神经系统淋巴瘤患者，但我们的主要假设没有得到证实。全脑放疗提供的无进展生存益处必须与长期生存者神经毒性风险增加相权衡。
Background High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival.Methods Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer-generated block randomisation to receive first-line chemotherapy based on high-dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age (= 60 years) and institution (Berlin vs Tubingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m(2)) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1.5 g/m(2)) on days 3-5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1.5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0.9. This trial is registered with ClinicalTrials.gov, number NCT00153530.Findings 551 patients (median age 63 years, IQR 55-69) were enrolled and randomised, of whom 318 were treated per protocol. In the per-protocol population, median overall survival was 32.4 months (95% CI 25.8-39.0) in patients receiving whole brain radiotherapy (n=154), and 37.1 months (27.5-46.7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1.06 (95% CI 0.80-1.40; p=0.71). Thus our primary hypothesis was not proven. Median progression-free survival was 18.3 months (95% CI 11.6-25.0) in patients receiving whole brain radiotherapy, and 11.9 months (7.3-16.5; p=0.14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%).Interpretation No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors.