比较大剂量氨甲蝶呤化疗加与不加全脑放疗治疗原发中枢的淋巴瘤的疗效：一项III期的非劣效性随机研究

中国肿瘤化疗  摘自：Lancet Oncol. 2010 Nov;11(11):1036-47.

背景：大剂量氨甲蝶呤是初诊的原发中枢的淋巴瘤的标准治疗。由于全脑放疗可能出现迟发的神经毒性，目前对其是否为标准治疗尚有争议。我们的研究旨在了解大剂量氨甲蝶呤为基础的一线化疗在总生存方面是否不劣于相同化疗加全脑放疗。武汉协和医院肿瘤中心刘红利

方法：来自75个中心的免疫功能正常的初诊的原发中枢的淋巴瘤患者在2000年5月至2009年5月间入组。入组病例随机分配接受大剂量氨甲蝶呤为基础的一线化疗加或不加序贯全脑放疗。随机号由计算机分组派生，按年龄（<60岁 vs ≥60 岁）和研究中心（柏林 vs 图宾根 vs 其它）分层。生物统计中心完成对病人的随机分配后通过传真通知病人所在的研究中心。完成随机分配后不对医生和病人设盲。2000年5月至2006年8月间入组的病例接受6程大剂量氨甲蝶呤化疗（D1，4 g/m(2)，14天重复）；2006年8月后入组的病例接受6程大剂量氨甲蝶呤（D1，4 g/m(2)，14天重复）加异环磷酰胺（D3-5，1.5 g/m(2)，14天重复）化疗。分配到组一线化疗序贯放疗组的病人，全脑放疗总量为45Gy（分30次完成，每次1.5Gy）。分配到一线化疗不加放疗组的病人，如果化疗不能达到CR，接受大剂量阿糖胞苷化疗。研究的主要目的是比较总生存时间。对按方案治疗的病人进行分析。本研究的假设是不加全脑放疗不影响总生存，非劣效的界值为0.9。

结果：随机入组了551例病人（中位年龄63岁，IQR 55-69），其中318例按方案接受治疗。在按方案接受治疗的病例中，加全脑放疗病例（n=154）的中位总生存时间为32.4月 (95% CI 25.8-39.0)，不加全脑放疗病例（n=164）的中位总生存时间为37.1月 (95% CI 27.5-46.7)，风险比1.06 (95% CI 0.80-1.40; p=0.71)。结果不能证明本研究的假设为真。加全脑放疗病例的中位无进展生存时间为18.3月 (95% CI 11.6-25.0)，不加全脑放疗病例的中位无进展生存时间为11.9月 (95% CI 7.3-16.5; p=0.14)。持续CR病例中，加全脑放疗组较不加全脑放疗组出现更多的治疗相关神经毒性（临床诊断22/45, 49%; 神经影像学诊断35/49, 71% vs 9/34, 26%; 16/35, 46%）。

阐释：初诊的原发中枢的淋巴瘤一线化疗后不加全脑放疗在总生存方面的疗效较一线化疗加全脑放疗无统计学差异，但不能证明不加全脑放疗不劣于加全脑放疗的假设。全脑放疗有改善无进展生存的趋势，但增加长期存活病例的神经毒性，需权衡利弊。

High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial.

Lancet Oncol. 2010 Nov;11(11):1036-47.

Abstract

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 vs ≥60 years) and institution (Berlin vs Tübingen 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.

PMID: 20970380