甲氨蝶呤鞘内注射化疗对肺癌脑膜转移的疗效分析

目的探讨鞘内注射甲氨蝶呤(MTX)治疗肺癌脑膜转移患者的临床疗效和预后影响因素。方法收集108例接受MTX鞘内注射化疗的肺癌脑膜转移患者的临床资料,分析MTX鞘内注射化疗的症状改善情况、脑脊液生化水平和总生存时间(OS),肺癌脑膜转移患者预后的影响因素采用COX风险比例模型。结果 108例肺癌脑膜转移患者中位OS为14个月。鞘内注射化疗后56例患者神经系统症状好转。与鞘内注射化疗前脑脊液生化水平比较,脑脊液蛋白含量降低,脑脊液葡萄糖含量升高,差异均有统计学意义(P<0.05)。COX多因素分析显示,卡式功能状态(KPS)评分≥60分、接受EGFR-TKI治疗是腰椎穿刺MTX鞘内注射化疗肺癌脑膜转移患者预后良好的独立保护因素,合并脑实质转移是其预后不良的独立危险因素。结论腰椎穿刺MTX鞘内注射化疗可改善患者临床症状,治疗安全有效。KPS评分≥60分、无脑实质转移的肺癌脑膜转移患者生存时间较长,联合应用EGFR-TKI治疗可改善接受MTX鞘内注射化疗的肺癌脑膜转移患者预后。     

脑膜癌病22例临床分析

目的探讨脑膜癌病（MC）的临床、磁共振（MRI）和脑脊液细胞学特点。方法回顾性分析22例脑膜癌病患者的临床表现、MRI、脑脊液细胞学改变。结果头痛是最常见的临床表现,发生率为81．8％;MRI可见脑积水和不同程度脑膜强化;腰穿压力增高,脑脊液检查发现细胞数高、蛋白增高,糖和氯化物降低,易于脑膜炎混淆,反复脑脊液细胞学检查可发现癌细胞,脑脊液免疫细胞化学检查可协助诊断。结论脑膜癌病临床症状无特异性,反复的脑脊液细胞学检查发现癌细胞对本病具有诊断意义,脑脊液免疫细胞化学检查可减少反复腰椎穿刺的痛苦。     

实体瘤脑膜转移鞘内药物治疗进展

实体瘤脑膜转移是肿瘤晚期一种灾难性的合并症,预后很差,目前缺乏有效的治疗方法。鞘内化疗作为脑膜转移癌治疗的一种方法,虽然得到了许多指南或者专家共识的推荐,在临床实践中也经常应用,但鞘内化疗的疗效一直缺乏高质量研究证据的支持。甲氨蝶呤、阿糖胞苷、塞替派等鞘内化疗常用的药物疗效并不理想。本文对新型鞘内注射药物的用法、疗效和安全性进行总结。     

脑膜癌病的研究进展

脑膜癌病（meningeal carcinomatosis,MC）又称癌性脑膜炎（neoplastic meningitis）,是癌症患者重要的神经系统并发症,在实体肿瘤患者中的发病率为1％～5％,在白血病和淋巴瘤患者中发病率为5％～15％,在原发性脑肿瘤患者中发病率为1％～2％,1％～7％的患者找不到肿瘤原发灶,解剖发现有神经系统受累症状和体征并被证实有脑膜受累证据的癌症患者发病率达19％,且随着患者生存时间的延长MC的发病率越高。     

脑膜癌病的诊治

目的　探讨脑膜癌病的诊治方法及预后。方法　结合文献对 10例脑膜癌病的临床资料进行分析。结果　 10例病人头颅CT平扫均正常 ,脑脊液均有改变 ,8例有脑电图改变 ,鞘内化疗可改善患者神经系统症状和体征。结论　脑脊液细胞学检查是诊断脑膜癌病的主要依据 ,本病目前尚无有效的治疗方法 ,脑膜癌病预后不良。     

胃癌转移致脑膜癌病临床分析

目的: 分析16例胃癌致脑膜癌病的临床特征。 方法: 对16例经脑脊液细胞学证实的胃癌致脑膜癌病患者的临床资料进行分析。 结果: 首发症状多为头痛、呕吐,头颅CT或MRI检查多无异常发现,脑脊液检查颅内压均有不同程度增高,脑脊液生化检查蛋白升高者多见,细胞学检查均见癌细胞,形态与原发肿瘤相似,经治疗后31.25%的患者获得缓解。 结论: 对以头痛、呕吐发病,伴颅内压增高及脑膜刺激征,且CT及MRI检查无明显异常者,应高度警惕脑膜癌病的可能,鞘内加全身化疗是有效的治疗手段。     

39例脑脊膜转移瘤诊治的临床分析

目的:通过分析软脑膜转移瘤的临床表现和不同治疗方案的疗效, 评价该病的诊断要点、首选的影像学检查方法和确诊指标, 探讨目前可行的最佳治疗方案。方法:39例软脑膜转移瘤患者, 全部行CT平扫, 其中29例行增强扫描;35例行MRI平扫, 其中26例行增强MRI扫描;给予放射治疗+鞘内化疗32例, 单行鞘内化疗3例, 单行放射治疗2例, 支持、对症治疗2例。结果:增强MRI扫描显示为4种表现:软脑膜受累、硬膜受累、脊膜受累及脑水肿, 33例行腰椎穿刺的患者显示18例蛛网膜下腔开放压力升高, 其中16例查见癌细胞;放疗+鞘内化疗组平均生存7周, 单纯鞘内化疗组平均生存4.5周, 局限性脑膜转移灶单纯放射治疗, 平均生存31.5周, 对症、支持治疗组, 平均生存4天。结论:对软脑膜转移的早期诊断和及时、正确的治疗可以防止神经系统进一步损害的发生, 延长患者的生存时间。增强MRI扫描是首选的影像学检查方法, 腰穿CSF细胞学检查为确诊的重要手段, 受累区的放射治疗和鞘内化疗是其主要的治疗措施。     

Phase II Study of Systemic High-dose Methotrexate and Intrathecal Liposomal Cytarabine for Treatment of Leptomeningeal Carcinomatosis From Breast Cancer

Metastatic breast cancer frequently leads to brain metastases and, less commonly, leptomeningeal carcinomatosis (LC). Once cerebrospinal fluid involvement occurs, the prognosis is poor. There are limited treatment options available, but none offer significant survival benefit. Methotrexate, given systemically at high doses (3.5-8 gm/m²), achieves cytotoxic concentrations in the CSF and has been shown to prolong survival in patients with LC. Intrathecal liposomal cytarabine has been shown to increase time to neurologic progression in patients with breast cancer and LC. The combination of these 2 agents in LC has not been studied extensively. Here, we present the results of the phase II study with this combination showing promising efficacy and very good tolerability.     

Intrathecal anti-CD20 antibody: an effective and safe treatment for leptomeningeal lymphoma

A patient with relapsed B cell non-Hodgkin lymphoma (NHL) infiltrating the Central nervous system (CNS) and resistant to chemotherapy was treated with intrathecal Rituximab (IT RTX), administered weekly for eight weeks at increasing doses, from 10 to 40 mg. After the second administration the patient showed significant clinical improvement and Cerebro spinal fluid (CSF) clearance of lymphomatous cells. A MRI scan performed after 30 days from the start of therapy showed full regression of lymphomatous infiltration. This report confirms the efficacy and safety of IT RTX in the treatment of CNS B-cell NHL.     

Leptomeningeal metastasis from ovarian carcinoma successfully treated by the intraventricular administration of methotrexate

A 60-year-old woman with a history of ovarian carcinoma and complaining of gait instability, dizziness, nausea, and a right temporal headache visited a neurologist. A diagnosis of leptomeningeal metastasis was made, based on the results of a cerebrospinal fluid examination. After the administration of intrathecal methotrexate, her neurological complaints disappeared. An Ommaya intraventricular reservoir was inserted, and methotrexate administration was continued for 11 months, until another recurrence was found in her pelvis. Although uncommon, the possibility of leptomeningeal metastasis from ovarian carcinoma should be considered; in such cases, treatment with intraventricular methotrexate may be effective and feasible and should be considered as a treatment strategy.     

Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration

Purpose: Intrathecal methotrexate achieves high concentrations in cerebrospinal fluid (CSF), but drug distribution throughout the subarachnoid space after an intralumbar dose is limited. The objective of this study was to quantify methotrexate distribution in CSF after intraventricular and intravenous administration and to identify factors that influence CSF distribution. Methods: Nonhuman primates (Macaca mulatta) with permanently implanted catheters in the lateral and fourth ventricles received methotrexate by bolus injection (0.5 mg) and infusion (0.05 to 0.5 mg/day over 24 to 168 h) into the lateral ventricle, as well as intravenous infusions. CSF was sampled from the lumbar space, fourth ventricle and the subarachnoid space at the vertex. Methotrexate in CSF and plasma was measured with the dihydrofolate reductase inhibition assay. Results: After bolus intraventricular injection, methotrexate exposure in lumbar CSF ranged from 11% to 69% of that achieved in the fourth ventricle. During continuous intraventricular infusions, methotrexate steady-state concentrations (C_ss) in lumbar CSF and CSF from the vertex were only 20% to 25% of the ventricular CSF C_ss. The dose, duration of infusion, and infusate volume did not influence drug distribution to the lumbar CSF, but probenicid increased the lumbar to ventricular C_ss ratio, suggesting the involvement of a probenicid-sensitive transport pump in the efflux of MTX from the CSF. During the intravenous infusions, the ventricular methotrexate C_ss was lower than the lumbar C_ss and the C_ss in CSF from the vertex. Conclusion: Methotrexate CSF distribution after intraventricular injection was uneven, and at steady-state CSF methotrexate concentrations were lower at sites that were more distant from the injection site. Received: 20 April 1999 / Accepted: 28 July 1999     

Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis

Purpose: To evaluate the pharmacokinetics and toxicity of high-dose intravenous (i.v.) methotrexate (MTX) with leucovorin in patients with meningeal carcinomatosis. Methods: Of 16 eligible patients entered on this study, 13 with meningeal carcinomatosis from breast cancer, lung cancer, or osteosarcoma were treated with MTX at loading doses of 200–1500 mg/m², followed by a 23-h infusion of 800–6000 mg/m². Three patients without meningeal disease were also treated and the cerebrospinal fluid (CSF) MTX concentrations were compared in patients with and without central nervous system (CNS) disease. Results: Patients without CNS disease had lower CSF MTX concentrations relative to the plasma MTX levels than those with CNS disease, who all had CSF MTX concentrations above the target cytotoxic concentration (1 μM). The CSF MTX concentrations correlated better with the free and the total plasma MTX concentrations than with the doses. The mean half-life of CSF MTX was 8.7 ± 3.4 h. The mean plasma clearance of MTX was not significantly different in patients with CNS disease (84 ± 41 ml/min per m²) versus without CNS disease (59 ± 38 ml/min per m²). All toxicities were grade 2 or less except grade 3 hematologic toxicity. No patient had an objective response in the CSF. Conclusion: This trial demonstrates that potentially cytotoxic CSF MTX concentrations (>1 μM) are delivered safely by i.v. infusion, a less invasive and better distributed CSF therapy compared with intrathecal MTX. Because of the excellent pharmacokinetics and toxicity, high-dose i.v. MTX should be evaluated at a loading dose of 700 mg/m² and a 23-h infusion of 2800 mg/m² with leucovorin in less heavily pretreated patients with carcinomatous meningitis. Received: 4 May 1999 / Accepted: 14 February 2000     

Continuous intrathecal treatment with methotrexate via subcutaneous port: implication for leptomeningeal dissemination of malignant tumors

Use of intrathecal (IT) chemotherapy combined with radiotherapy can extend survival of patients with untreated leptomeningeal dissemination of malignant tumors from one month to two to six months. The goal of the present study was to determine the effect of continuous IT (CIT) via a subcutaneous port that was placed using a neuronavigation system. Twenty patients with leptomeningeal dissemination (primary disease: 10 cancers, 6 gliomas and 4 lymphomas) were given 2–7 cycles of continuous IT (CIT) with methotrexate (MTX; 10 mg) administered into the lateral ventricle for 5 consecutive days biweekly. The concentration of MTX in the lateral ventricle was 7 to 10 × 10⁻⁶ M from Day 1 to 4. Response to this therapy included 6 patients with complete remission, 7 with progressive disease, and 7 with stable disease. Kaplan-Meier analysis revealed a median overall survival of 8 months while the overall survival rate for leptomeningeal specific death or for metastasis from cancer was 13 or 5 months, respectively. Complications of CIT with MTX were relatively low (<0.5%), and nausea and vomiting did not occur in any of the patients. In conclusion, CIT with 10 mg MTX via subcutaneous port for 5 days may improve the therapeutic effect and reduce the complications associated with treatment of leptomeningeal dissemination from malignant tumors. This would be a safe technique with possible implications that bear repeating more patients. N. Shinoura and Y. Tabei have equally contributed to this work.     

Therapy of leptomeningeal metastasis in solid tumors

Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage complication of various solid tumors. Clinical signs and symptoms may include cranial nerve palsies, radicular symptoms, signs of increased intracranial pressure such as headache, nausea and vomiting, and cognitive dysfunction. In cases of suspected LM, the highest diagnostic sensitivity is provided by the combination of CSF cytology and contrast-enhanced MRI (cranial as well as complete spine). The therapeutic spectrum includes radiotherapy of the clinically involved region as well as systemic and intrathecal chemotherapy. The choice of treatment modalities depends on the type of LM (non-adherent tumor cells in the CSF vs. nodular contrast-enhancing tumor growth), additional systemic involvement (uncontrolled vs. controlled systemic disease) and additional involvement of the CNS parenchyma (LM as the only CNS involvement vs. LM + parenchymal CNS metastases). Larger contrast-enhancing nodular LM or symptomatic lesions of the spine may be treated with radiotherapy. In case of uncontrolled systemic disease, the treatment regimen should include systemic chemotherapy. The choice of systemic treatment should take into account the histology of the primary tumor. Intrathecal chemotherapy is most important in cases of LM of the non-adherent type. There are three substances for routine use for intrathecal chemotherapy: methotrexate, cytarabine, and thiotepa. Liposomal cytarabine shows advantages in terms of longer injection intervals, a sufficient distribution in the entire subarachnoid space after lumbar administration and improved quality-of-life. The role of new agents (e.g. rituximab and trastuzumab) for intrathecal therapy is still unclear.     

正元胶囊辅助甲氨蝶呤治疗儿童急性淋巴细胞白血病的有效性和安全性分析

目的探讨正元胶囊辅助甲氨蝶呤治疗儿童急性淋巴细胞白血病的有效性和安全性以及对血清中B淋巴细胞刺激因子(BAFF)和增殖诱导配体(APRIL)水平的影响。方法 78例儿童急性淋巴细胞白血病随机分为对照组和观察组,各39例。对照组采取甲氨蝶呤治疗,观察组在对照组基础上于缓解期口服正元胶囊,1~3粒/次,3次/天,共治疗8周。比较2组近期疗效、治疗过程中不良反应。检测2组患儿血清中BAFF和APRIL水平。结果观察组近期总缓解率为89.74%,显著高于对照组的61.54%(P<0.01)。观察组患儿的口腔黏膜损害、肝功能损害、感染、骨髓抑制、胃肠道反应及皮肤损害发生少于对照组,但组间差异无统计学意义(P>0.05)。治疗后,观察组患儿血清中BAFF和APRIL水平显著低于对照组,差异有统计学意义(P<0.01)。结论金正元胶囊辅助甲氨蝶呤治疗儿童急性淋巴细胞白血病的疗效确切,安全性好,降低患儿血清中BAFF和APRIL水平可能与其疗效有关。