Objective: To investigate the feasibility, safety and efficacy of intrathecal pemetrexed (IP) treated for patients with leptomeningeal metastases (LM) from solid tumors. Methods: Forty-seven patients receiving pemetrexed intrathecal chemotherapy in the First Hospital of Jilin University from 2017 to 2018 were selected. The study of pemetrexed intrathecal chemotherapy adopted the classical dose-climbing model and included 13 patients with meningeal metastasis of non-small cell lung cancer who had relapsed and refractory after multiple previous treatments including intrathecal chemotherapy. Based on the dose climbing study, 34 patients with meningeal metastasis of solid tumor who did not receive intrathecal chemotherapy were enrolled in a clinical study using pemetrexed as the first-line intrathecal chemotherapy combined with radiotherapy. Kaplan-Meier method and Log rank test were used for survival analysis, and Cox regression model was used for influencing factor analysis. Results: The dose climbing study showed that the maximum tolerated dose of pemetrexed intrathecal chemotherapy was 10 mg per single dose, and the recommended dosing regimen was 10 mg once or twice a week. The incidence of adverse reactions was 10 cases, including hematological adverse reactions (7 cases), transaminase elevation (2 cases), nerve root reactions (5 cases), fatigue and weight loss (1 case). The incidence of serious adverse reactions was 4, including grade 4-5 poor hematology (2 cases), grade 4 nerve root irritation (2 cases), and grade 4 elevated aminotransferase (1 case). In the dose climbing study, 4 patients were effectively treated and 7 were disease controlled. The survival time was ranged from 0.3 to 14.0 months and a median survival time was 3.8 months. The clinical study of pemetrexed intrathecal chemotherapy combined with radiotherapy showed that the treatment mode of 10 mg pemetrexed intrathecal chemotherapy once a week combined with synchronous involved area radiotherapy 40 Gy/4 weeks had a high safety and reactivity. The incidence of major adverse reactions was 52.9% (18/34), including hematologic adverse reactions (13 cases), transaminase elevation (10 cases), and nerve root reactions (4 cases). In study 2, the response rate was 67.6% (23/34), the disease control rate was 73.5% (25/34), the overall survival time was ranged from 0.3 to 16.6 months, the median survival time was 5.5 months, and the 1-year survival rate was 21.6%. Clinical response, improvement of neurological dysfunction, completion of concurrent therapy and subsequent systemic therapy were associated with the overall survival (all P<0.05). Conclusions: Pemetrexed is suitable for the intrathecal chemotherapy with a high safety and efficacy. The recommended administration regimen was IP at 10 mg on the schedule of once or twice per week. Hematological toxicity is the main factor affecting the implementation of IP. Vitamin supplement can effectively control the occurrence of hematological toxicity.
目的： 探讨培美曲塞鞘内化疗治疗实体肿瘤脑膜转移的可行性、安全性及反应性。 方法： 选取2017—2018年于吉林大学第一医院采用培美曲塞鞘内化疗的47例患者。培美曲塞鞘内化疗研究采用经典剂量爬坡研究模式，纳入13例既往经过鞘内化疗等多种治疗后复发难治的非小细胞肺癌脑膜转移患者。基于剂量爬坡研究，进行培美曲塞一线鞘内化疗联合放疗临床研究，纳入未接受过鞘内化疗的实体肿瘤脑膜转移患者34例。生存分析采用Kaplan-Meier法和Log rank检验，影响因素分析采用Cox回归模型。 结果： 剂量爬坡研究显示，培美曲塞鞘内化疗最大耐受剂量为单次10 mg，推荐给药方案为10 mg，每周1~2次给药。10例发生不良反应，包括血液学不良反应(7例)、转氨酶升高(2例)、神经根反应(5例)及乏力和体重下降(1例)；4例发生严重不良反应，包括4~5级血液学不良反应(2例)、4级神经根刺激症状(2例)和4级转氨酶升高(1例)。剂量爬坡研究治疗有效患者为4例，疾病控制患者7例，生存时间为0.3~14.0个月，中位生存时间为3.8个月。培美曲塞鞘内化疗联合放疗临床研究显示，每周1次10 mg培美曲塞鞘内化疗，联合同步受累区放疗40 Gy/4周的治疗模式具有较高的安全性及反应性。主要不良反应发生率为52.9% (18/34)，包括血液学不良反应(13例)、转氨酶升高(10例)和神经根反应(4例)。研究2患者治疗反应率为67.6% (23/34)，疾病控制率为73.5% (25/34)，总生存时间为0.3~16.6个月，中位生存时间为5.5个月，1年生存率为21.6%。临床治疗反应、神经功能障碍改善、完成同步治疗、后续进行系统治疗与总生存有关(均P<0.05)。 结论： 培美曲塞适用于鞘内化疗给药，具有较高的安全性及反应性。推荐给药方案为单次剂量10 mg，每周1~2次。血液学不良反应为影响培美曲塞鞘内化疗实施的主要因素，应用维生素补充可有效控制血液学不良反应发生。.
Keywords: Intrathecal chemotherapy; Leptomeningeal metastasis; Malignant solid tumors; Pemetrexed.