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。     

肺癌脑膜转移诊治现状

脑膜转移又称“癌性脑膜炎”或“脑膜癌病”,是恶性肿瘤的一种严重并发症,尸检研究提示有神经症状和体征的癌症患者19％有脑膜累及。各种不同类型肿瘤的脑膜转移发生率不一样,在大宗脑膜转移的病例分析中,原发肿瘤是肺癌的较为多见。继发于肺癌的脑膜癌病发病率约2％,虽然很低,但由于早期诊断困难、治疗效果差等原因,导致患者预后不良。     

脑膜转移瘤22例的临床诊治及预后

目的：研究恶性肿瘤脑膜转移的临床诊断、治疗方法以及预后。方法：对22例脑膜转移瘤的临床资料进行回顾性分析。结果：22病例中，有明确影像诊断者20例，CSF细胞学诊断者6例，21例分别接受鞘内化疗、局部放射、全身化疗等治疗，总生存期1周-15月，中位生存期3月。结论：脑膜转移是癌症的一个最严重的并发症之一，预后较差，诊断主要依靠CSF细胞学和MRI，治疗手段有全身化疗、鞘内治疗、局部放射治疗等。     

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。     

鞘内及全身化疗治疗脑转移瘤23例

自1992年5月至2002年10月我们对23例脑转移瘤患者行鞘内化疗结合全身化疗,取得了较好疗效,现报告如下.     

63例脑膜转移瘤临床分析

目的 探讨脑膜转移瘤(CM)的临床表现和治疗方法及其与预后关系.方法 回顾本院1998-2008年确诊的63例CM患者病历资料,分析其临床表现及不同治疗方式与预后关系.63例CM患者中原发灶以肺癌(65%)及乳腺癌(13%)多见.所有患者均经增强MRI检查,29例患者同时行腰穿检查.51例患者接受了全脑放疗、全身化疗和(或)鞘内化疗,其余12例患者单纯对症支持治疗.采用Kaplan-Meier法进行生存分析.结果 所有患者在随访期内全部死亡,随访率为95%,其中随访满1、2年者分别为59、56例.全组患者中位总生存期为2.2个月(0.1～24.4个月).确诊CM前临床分期(x2=6.68,P=0.036)及原发灶控制情况(x2=7.04,P=0.008)与生存明显相关.放疗剂量≥30 Gy者与未放疗者中位生存期分别为3.0个月(1.0～24.4个月)和1.8个月(0.1～14.2个月)(x2=5.54,P=0.019);放疗±化疗组、单纯化疗组及单纯对症治疗组中位生存期分别为3.0个月(0.5～24.4个月)、2.2个月(0.3～14.2个月)和1.2个月(0.1～4.5个月)(x2=9.32,P=0.009).结论 CM预后较差,CM前临床分期及原发灶控制情况与生存明显相关,足量放疗有望延长患者生存期,但尚需大样本临床研究证实.

Abstract：

Objective To analyze the clinical characteristics and the prognostic factors of carcinomatous meningitis(CM). Methods 63 patients with CM treated in Tianjin Medical University Cancer Institute and Hospital from 1998 to 2008 were reviewed retrospectively. The correlations between clinical characteristics, treatment modalities and the prognosis of CM were analyzed. The common primary site was lung cancer(65%)and breast cancer(13%). All the patients were underwent MRI scan and 29 of the patients received lumbar puncture. Fifty-one patients received whole brain radiotherapy, systemic and/or intrathecal chemotherapy. The other 12 patients only received supportive care. Kaplan-Meier method and Log-rank test were used for survival analysis. Results All patients died by the end of follow-up. The follow-up rate was 95%. The number of patients who undergone 1-,2 years follow-up were 59 and 56. The median survival time was 2. 2 months(range :0. 1 -24. 4 months)for the entire group. The clinical stage and the control status of the primary disease were strongly correlated with survival(x2 = 6. 68, P = 0. 036)and(x2 = 7.04, P = 0. 008). The median survival time was 3.0 months(range: 1.0 - 24. 4 months)in patients who received ≥30 Gy whole brain irradiation, while only 1.8 months(range:0. 1-14. 2 months)in those who did not receive radiotherapy(x2 =5.54,P =0. 019). The median survival time of radiotherapy ± chemotherapy group, chemotherapy only group and supportive treatment only group were 3.0 months (range :0. 5 - 24. 4 months), 2. 2 months(range :0. 3 - 14. 2 months)and 1. 2 months(range :0. 1 - 4.5 months), respectively(x2 = 9. 32, P = 0. 009). Conclusions The prognosis of CM is very poor. The clinical stage before the diagnosis of CM and the control status of primary disease and were significantly correlated with survival. Sufficient whole brain irradiation dose may prolong survival and worth further study in a large sample study.     

恶性肿瘤的脑膜转移

脑膜转移是恶性肿瘤最严重的并发症之一,约见于5%的所有恶性肿瘤,预后差.诊断主要依靠脑脊液细胞学和影像学检查,现有的治疗属姑息性,包括全身化疗、鞘内治疗、局部放射治疗等.     

实体瘤脑膜转移的放射治疗（附5例报告）

目的研究实体瘤脑膜转移的放射治疗疗效。方法5例临床诊断为脑膜转移癌患者行全脑放疗。结果5例中有1例因恶液质未能完成放疗,其余4例患者临床症状改善,其中2例MR上病灶缩小。结论放射治疗是改善脑膜转移癌症状的一种有效手段。     

培美曲塞鞘内化疗治疗实体肿瘤脑膜转移的临床研究

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...     

Leptomeningeal metastasis

Leptomeningeal metastasis is a common complication of cancer. Often the diagnosis can be difficult, but early diagnosis and aggressive treatment can prevent irreversible neurologic deficits. Diagnosis is usually established by the demonstration of malignant cells in the cerebrospinal fluid (CSF) or by the presence of enhancing tumor nodules on cranial or spinal MRI. Treatment may require focal radiotherapy to symptomatic sites accompanied by chemotherapy. Intra-CSF chemotherapy requires normal CSF flow dynamics and is typically limited to the use of methotrexate, cytarabine or thiotepa. Intrathecal chemotherapy is rarely efficacious, except for hematopoietic neoplasms and, to a lesser extent, breast cancer. Increasingly, systemic chemotherapy is recognized as efficacious in the treatment of leptomeningeal metastasis in part because it has the ability to penetrate into bulky disease seen on neuroimaging. The optimum choice of therapy depends upon a thorough assessment of the neurologic extent of disease, which should include complete neuraxis imaging. Patients with extensive bulky disease may be best treated with systemic chemotherapy, whereas those with a positive CSF cytology but negative imaging may be treated with intrathecal chemotherapy and spared the systemic toxicity of intravenous drug. Despite vigorous therapy, many patients do poorly and the median survival is only about four months. Nevertheless, some patients, particularly those with leukemia, lymphoma, and breast cancer, respond and a substantial minority will be alive one to two years after diagnosis.     

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.     

Leptomeningeal carcinomatosis from gastric cancer successfully treated by the intrathecal methotrexate plus temozolomide and simultaneous radiotherapy: Case report and literatures review

Leptomeningeal carcinomatosis (LMC) from gastrointestinal cancer is rare. A 56-year-old man with complaint of upper abdominal pain exhibited adenocarcinoma upon histopathologic examination of biopsy specimens. At the end of adjuvant chemotherapy, the patient was affected by hearing loss. Malignant cells were observed by cerebrospinal fluid (CSF) cytology. Therefore, the patient received intrathecal methotrexate and oral temozolomide chemotherapy and radiotherapy. The progress-free survival was approximately 11 months. To our knowledge, such cases of LMC from gastric cancer are very rare. Here, we describe the case of a patient with LMC from gastric cancer and review the literature associated with treatment. We hope that the present report may be helpful when considering how to improve treatment of LMC in gastric cancer patients and offer some tips for the adjuvant treatment modality.     

Efficacy and Safety of Intrathecal Pemetrexed Combined With Dexamethasone for Treating Tyrosine Kinase Inhibitor-Failed Leptomeningeal Metastases From EGFR-Mutant NSCLC—a Prospective,Open-Label,Single-Arm Phase 1/2 Clinical Trial (Unique Identifier: ChiCTR1800016615)

IntroductionWe aimed to evaluate the efficacy and safety of intrathecal pemetrexed (IP) for treating EGFR-mutant leptomeningeal metastases (LMs) from EGFR-mutant NSCLC.MethodsPatients with EGFR-mutant NSCLC with LM who had failed tyrosine kinase inhibitors were recruited. The dose of IP was escalated from 15 mg to 80 mg using an accelerated titration design in a phase 1 study. The recommended dose (RD) determined in phase 1 was used in the phase 2 study. The primary end point was treatment efficacy measured as the clinical response rate. Overall survival and adverse events (AEs) were evaluated as secondary end points.ResultsThe RD observed in the phase 1 study was 50 mg pemetrexed. A total of 30 cases of LM-NSCLC were enrolled in the phase 2 study, including 14 males and 16 females. Four patients did not survive for 4 weeks and could not be evaluated for efficacy. The clinical response rate was 84.6% (22 of 26). The median overall survival of all patients was 9.0 months (n = 30, 95% confidence interval: 6.6–11.4 mo). Most AEs were mild, and the most frequent AE of any grade was myelosuppression (n = 9, 30%), which returned to normal after symptomatic treatment.ConclusionsThis study revealed that 50 mg pemetrexed is the RD which results in few AEs and a good response rate. IP is an effective treatment for patients with EGFR-mutant NSCLC-LM who had failed on tyrosine kinase inhibitor.     

甲氨蝶呤鞘内注射治疗脑膜癌病疗效和安全性的临床观察

背景与目的脑膜癌病是中枢神经系统转移瘤的一种少见类型。近年来,随着恶性肿瘤治疗疗效的提高,患者生存期延长,脑膜癌病的发病率逐年增加,目前尚缺乏有效的治疗手段。本研究旨在探讨鞘内注射甲氨蝶呤（methotrexate, MTX）治疗脑膜转移的疗效、安全性和预后。方法对27例脑膜转移患者的临床资料、脑脊液实验室检查进行回顾性分析,并分析鞘注化疗后的不良反应及预后。结果27例脑膜转移患者接受鞘注化疗后,70.4%获得临床症状缓解,但脑脊液压力和脑脊液生化改变无统计学差异。55.6%患者无不适,25.9%出现下肢麻木、轻微疼痛,无严重不可逆的不良反应发生。本组患者中位生存期4个月。结论鞘内注射MTX可改善脑膜癌病患者临床症状,无严重不良反应发生。     

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.