原发中枢神经系统淋巴瘤治疗进展

 【摘要】　原发性中枢神经系统淋巴瘤（PCNSL）是原发于脑、眼和脊髓的结外淋巴瘤,发病率低,老年患者多见,因其在庇护所内恶性侵袭性生长,使得治疗困难,预后不良。目前PCNSL尚无标准治疗方法,有效的治疗一般采用化疗和放疗联合的措施。手术不能完全切除病灶,仅起到诊断作用。大剂量甲氨蝶呤（HD-MTX）是最有效的药物,大剂量阿糖胞苷是常用的药物之一。PCNSL对放疗高度敏感,但单纯放疗有效维持时间短,对60岁以上患者可导致严重的远期神经毒性,影响预后,故主张延迟放疗。大剂量化疗联合自体干细胞移植通过提高剂量化疗可以克服肿瘤细胞耐药,提高药物生物利用度,替代全脑放疗,减少神经毒性。新药替莫唑胺、利妥昔单抗等对PCNSL取得一定效果,值得进一步研究。     

原发性中枢神经系统淋巴瘤的治疗进展

原发性中枢神经系统淋巴瘤（PCNSL）是一种少见疾病,至今尚无标准治疗方案。单纯放疗复发率高,生存期短。放疗宜在化疗结束后进行。化疗联合标准放疗明显降低了复发率,并延长了生存期,但神经毒性发生率高。老年患者易出现神经毒性,不建议放疗,应首选单纯化疗;年轻患者可将放疗作为难治复发时的二线治疗。目前,以大剂量甲氨蝶呤为主的化疗已成为PCNSL的一线治疗,大剂量阿糖胞苷为最常联合的药物。年轻患者可选用包含一些新药如甲基苄肼、替莫唑胺的化疗方案。替莫唑胺为老年患者一种有前途的新药。预防性鞘内化疗的必要性尚未达成共识。自体造血干细胞支持下的大剂量化疗对年轻的初发及复发PCNSL患者均有效。手术通常用于PCNSL诊断。糖皮质激素不宜在取得病理组织前使用。      

原发性中枢神经系统淋巴瘤的高剂量MTX化疗加放疗——附17例临床疗效分析

背景和目的：原发性中枢神经系统淋巴瘤(Primary central nervous systemlym phoma，PCNSL)是一种罕见的原发并局限于脑和脊髓的非霍奇金氏淋巴瘤，治疗上主要采用高剂量MTX(HD—MTX)为主的化疗及放射治疗。本文探讨HD—MTX为主的化疗及放疗对PCNSL的疗效及毒性。方法：回顾性分析1991～2004年间我院收治的17例PCNSL患者的临床资料。其中，单纯CHOP方案化疗2例，含HD—MTX方案化疗12例，MTX／Ara—C／DXM鞘内注射9例。13例患者接受放射治疗。其中，单纯全脑放疗2例，全脑 局部缩野照射8例，全中枢放疗2例；侵犯野照射1例。结果：随访时间最长120个月，中位随访时间24个月。死亡4例，2例死于肿瘤进展，1例死于复发，1例死于放化疗后感染。结论：含HD—MTX为主的化疗联合全脑照射是PCNSL治疗的主要模式，治疗毒性可以耐受。放疗在PCNSL治疗中的地位有待进一步研究。     

原发性中枢神经系统淋巴瘤诊治进展

原发性中枢神经系统淋巴瘤(primarycentralnervoussystemlymphoma,PCNSL)是原发于脑、眼和脊髓的非霍奇金氏淋巴瘤,临床上较罕见,近数十年来发病率逐渐上升。PCNSL多见于老年患者,病理类型、预后因素和治疗方案有别于全身性非霍奇金淋巴瘤(NHL)。PCNSL病理类型以弥漫大B细胞为主,年龄和(performancestatus)PS是最重要的预后因素,预后较全身性NHL差。目前PCNSL尚无标准治疗方法,一般采用化疗和放疗联合的治疗措施。手术仅起到诊断作用。PCNSL对放疗高度敏感,但单纯放疗有效维持时间短。化疗在治疗PCNSL中不可缺少,但CHOP方案对PCNSL无效。大剂量甲氨蝶呤(HD-MTX)是最有效的药物,大剂量阿糖胞苷(HD-AraC)是常用的药物之一。因此,现阶段PCNSL采用含HD-MTX或/和HD-AraC等的联合化疗,同时鞘内注射MTX、AraC和地塞米松(DXM)。放疗疗效差,放疗应在化疗结束后进行。联合化、放疗对60岁以上患者可造成严重的远期神经毒性,对老年患者可选择单纯化疗和延迟放疗的治疗方法。自体造血干细胞支持下超大剂量化疗疗效优于历史对照。新药Temozolomide、Temozolomide联合美罗华、Topotecan、放射免疫治疗药物Y90标记CD20单抗等对PCNSL取得一定效果,值得进一步研究。     

大剂量甲氨蝶呤联合放疗治疗１９例原发性中枢神经系统淋巴瘤的临床观察

目的　观察大剂量甲氨喋呤联合放疗治疗原发性中枢神经系统淋巴瘤的疗效。方法　２００３年１月至２００８年２月我院经手术或立体定向活检病理证实的１９例原发性中枢神经系统淋巴瘤患者,予大剂量甲氨蝶呤化疗５～８个周期及阿糖胞苷＋地塞米松鞘内注射１２～１６次,序贯全脑放疗３０Ｇｙ,缩野１０Ｇｙ。结果　１９例患者中位生存期为４４个月,预计５年生存率为２８.６％。毒副作用以骨髓抑制（１００％）及胃肠道反应（7７％）多见,其次为肝肾功能损害、口腔炎及脱发等。毒副反应多数可耐受。结论　大剂量甲氨蝶呤化疗及阿糖胞苷＋地塞米松鞘内注射序贯放疗治疗原发性中枢神经系统淋巴瘤的疗效满意,安全性好。     

脑原发淋巴瘤8例综合治疗分析

目的分析脑原发淋巴瘤的临床特点,探讨其治疗方式。方法8例脑原发淋巴瘤中7例行手术切除,1例行立体定向活检。8例均行放射治疗,1例接受γ刀治疗,7例6MV X线常规分割照射,全脑照射30～46 Gy,病灶区剂量40～56 Gy。6例接受了化疗,行CHOP方案4例,大剂量甲氨蝶呤(MTX)为主的化疗2例,鞘注MTX 3例。结果患者近期疗效好,全组生存时间为8～47个月,中位生存期19个月。1、3年生存率分别为75.0%和31.3%。加化疗未延长生存期,予MTX化疗者生存时间较长。结论脑原发淋巴瘤预后差,全脑放疗为主要治疗方式之一,放疗与MTX为主的化疗方案的综合治疗有可能提高疗效。     

原发性中枢神经系统淋巴瘤的放射治疗

原发性中枢神经系统淋巴瘤可分为非免疫抑制和免疫抑制两种类型，前者预后较好，后者预后较差。目前放疗方法是全脑照射40～45Gy后，肿瘤原发部位局部推量到60～65Gy。化、放综合治疗可提高生存率，MTX静脉和鞘内化疗后再给予全脑放疗不会增加放射性脑病的发生率。最佳的治疗方式尚需要进一步的临床探讨。     

替莫唑胺为主的化疗联合放疗治疗原发中枢神经系统淋巴瘤的临床观察

  目的  评价以替莫唑胺为主的化疗联合放疗治疗原发中枢神经系统淋巴瘤(PCNSL)的疗效及不良反应。   方法  对2006年6月至2012年3月山东省肿瘤医院收治的24例PCNSL患者采用全脑放疗同步替莫唑胺化疗之后, 给予替莫唑胺+奈达铂+长春新碱化疗方案行6~8个周期的辅助化疗。观察患者肿瘤缓解状态、总生存期及不良反应。   结果  24例均完成治疗。随访3~63个月, 中位生存时间为25个月, 治疗后CR者41.7%(10/24), PR者29.2%(7/24), SD者12.5%(3/24), PD者16.7%(4/24), 客观肿瘤缓解率(ORR)为70.8%。Kaplan-Meier分析显示该治疗方案优于大剂量甲氨蝶呤(HD-MTX)联合放疗治疗PCNSL的效果, 亦优于单药替莫唑胺治疗PCNSL的效果, 且不良反应小。   结论   替莫唑胺为主的化疗联合放疗治疗PCNSL较安全、效果好。      

原发性中枢神经系统淋巴瘤研究进展

原发性中枢神经系统淋巴瘤（Primary Central Nervous System Lymphoma,PCNSL）是一种比较罕见的结外淋巴瘤.好发于免疫缺陷的人群中.但近年来在免疫力正常人群中发病率不断增加,目前其发病机制仍有争论.其病理形态与颅外淋巴瘤相似,病理类型一般为中高度恶性非霍奇金淋巴瘤（NHL）,多为弥漫型大B细胞来源,来源于T细胞的比较少见.影像学表现为单发或多发的深部脑实质或血管周围病变及脑膜等处的病变.CT平扫呈圆形或卵圆形等密度占位病变,边界相对清楚,周围有水肿带,应与胶质瘤、脑膜瘤、转移瘤鉴别.脑脊液淋巴细胞亚群的流式分析能够对诊断脑膜淋巴瘤有所帮助.在临床表现方面与其它颅内肿瘤无明显差异.放化疗综合治疗有可能提高治愈率.化疗采用以MTX为主的化疗,全脑放疗已被公认为治疗PCNSL的有效手段.放、化疗的顺序在一定程度上可能影响患者的生存期,目前推荐采用先放后化的治疗方法.预后取决于多种因素如年龄、确诊时间、病变部位、肿瘤组织类型、治疗措施的选择、患者有否免疫抑制状态等.     

原发性中枢神经系统淋巴瘤的预后因素和治疗进展

原发性中枢神经系统淋巴瘤(PCNSL)是原发于脑和脊髓的非霍奇金氏淋巴瘤(NHL)，临床上较罕见，仅占脑肿瘤的1％和结外NHL的1％-2％。近数十年来发病率逐渐上升。由于部位特殊，现有NHL的预后因素和治疗原则不适用于PCNSL。PCNSL发病率低，目前尚无标准的预后因素和一线标准治疗方案，但随着临床治疗经验的不断积累，在治疗上已取得一定的共识，使PCNSL中位生存期由早年单纯放疗的13-16个月增加到目前综合治疗的30-36个月，疗效有较明显提高。本文着重于评述近年来在免疫功能正常的PCNSL预后因素的确立和临床治疗方面取得的进展。目前PCNSL一般采用化疗和放疗联合的治疗措施，手术仅起到诊断作用。化疗在治疗PCNSL中不可缺少，但CHOP方案对PCNSL几乎无效。大剂量甲氨蝶呤(HD—MTX)是最有效的药物，大剂量阿糖胞苷(HD—Ara—C)是另一个常用的有效药物，鞘内给药有助于预防脑脊髓膜的肿瘤种植。PCNSL对放疗高度敏感，但单纯放疗复发率高，远期疗效差，放疗应在化疗完成后进行，多常用全颅加侵犯野放疗。为降低化放疗的远期神经毒性，有人尝试采用单纯化疔治疗PCNSL，对于获得完全缓解的患者放疗延迟至复发后再进行，远期疗效有待确定。自体造血干细胞移植支持下超大剂量化疗和抗CD20单克隆抗体也试用于治疗PCNSL，取得一定效果。目前全身HD—MTX、化疗后放疗的次序、年龄和PS是PCNSL最重要的预后因素。因此，采用含HD—MTX或／和HD—Ara—C等的联合化疔，同时鞘内注射MTX、Ara—C和地塞米松(DXM)，结合颅脑放疗是现阶段治疗PCNSL最常用的治疗模式。     

Primäre ZNS-Lymphome

Primary CNS lymphomas (PCNSL) are rare brain tumors comprising only 3% of all primary intracranial neoplasms. The median age at diagnosis ranges between 60 and 65 years. PCNSLs often cause a rapidly progressing psychosyndrome. Magnetic resonance imaging (MRI) reveals multiple or single lesions with homogenous contrast enhancement often in the vicinity of the ventricles. The diagnostic method of choice is stereotactic biopsy. In more than 90% of cases a highly malignant B-cell non-Hodgkin’s lymphoma of the diffuse large-cell type is diagnosed. Patients should be included in clinical studies in order to optimize therapy. Patients younger than 60 years old are expected to be treated curatively and should receive polychemotherapy including systemic high-dose methotrexate (MTX). The role of high-dose chemotherapy with autologous stem cell transplantation as primary treatment has not finally been defined. For patients older than 60 years a curative treatment strategy is not established and in addition, toxicity plays a major role. A MTX-based chemotherapy, e.g. in combination with ifosfamide or temozolomide can be administered. Radiotherapy alone as primary treatment is not recommended. Combination radiotherapy with MTX-based chemotherapy is also not established, demonstrating a high rate of neurotoxicity at late follow-up. In the case of recurrence there are a number of possible treatment options depending on the primary therapy. In Germany, several study groups are organized and the aim of these consortia is optimization of PCNSL therapy.     

Recent advances in primary CNS lymphoma

PURPOSE OF REVIEW: This review highlights the recent advances in the pathogenesis and treatment of primary CNS lymphoma (PCNSL) in the immunocompetent population. RECENT FINDINGS: High-dose methotrexate (MTX)-based chemotherapy followed by whole brain radiotherapy represents the standard treatment. However, combined treatment exposes the patients to the risk of delayed neurotoxicity. Although this complication is less frequent and severe in young patients (less than 60 years) than in the elderly, neuropsychometric evaluation suggests that it is underestimated in this population. Recent trials, adding further to previous studies, suggest that high-dose MTX-based chemotherapy with deferred radiotherapy allows comparable results to those reported after combined chemoradiotherapy, with much better neurocognitive preservation. Intensive chemotherapy with autologous stem cell transplantation has shown a promising activity in relapsed or refractory PCNSL, but its value as first-line treatment compared with conventional treatment remains questionable. New therapeutic agents such as temozolomide, topotecan, or intrathecal rituximab (anti-CD20 monoclonal antibody) have demonstrated a modest but true activity as single-agent therapy in relapsed PCNSL and are of interest, in terms of their good safety profile, for inclusion in new polychemotherapy regimen as primary treatment. SUMMARY: In the elderly, MTX-based chemotherapy seems to be the best approach to achieve effective tumor control without compromising patient quality of life. Future trials should first analyze the value of radiotherapy as consolidation treatment in young patients (less than 60 years) who have achieved a remission after induction chemotherapy in a randomized study. Other trials are needed to further evaluate intensive chemotherapy with autologous stem cell transplantation both as primary and salvage therapy; and to investigate new drug combinations with high-dose MTX.     

Primary central nervous system lymphomas

Opinion statement Primary central nervous system lymphoma (PCNSL) is widely regarded as one of the primary brain tumors most amenable to treatment. Although whole brain radiotherapy was the cornerstone of therapy for decades, recent work clearly indicates that chemotherapy has become the primary focus of treatment for this disease. The initial treatment of PCNSL for all patients, including the elderly, should be chemotherapy using a high-dose methotrexate-based regimen. Although cranial irradiation has often been combined with methotrexate, the unacceptably high incidence of late neurotoxicity, particularly in older patients, has caused many to eliminate radiotherapy, especially in those older than age 60 years. Emerging data support the validity of this approach, and the development of more efficacious chemotherapeutic regimens has been the focus of recent research.     

Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy.

PURPOSE: To evaluate response rate, response duration, overall survival (OS), and toxicity in primary CNS lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy. PATIENTS AND METHODS: From September 1995 to July 2001, 65 consecutive patients with PCNSL (median age, 62 years) were enrolled onto a pilot and phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX; cycles 1, 2, 4, and 5) and cytarabine (ARA-C; cycles 3 and 6)-based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ARA-C. RESULTS: Sixty-one of 65 patients were assessable for response. Of these, 37 patients (61%) achieved complete response, six (10%) achieved partial response, and 12 (19%) progressed under therapy. Six (9%) of 65 patients died because of treatment-related complications. Follow-up is 0 to 87 months (median, 26 months). The Kaplan-Meier estimates for median time to treatment failure (TTF) and median OS were 21 months and 50 months, respectively. For patients older than 60 years, median survival was 34 months, and the median TTF was 15 months. In patients younger than 61 years, median survival and median TTF have not been reached yet; the 5-year survival fraction is 75%. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 12 patients (19%), and permanent cognitive dysfunction possibly as a result of treatment occurred in only two patients (3%). CONCLUSION: Primary chemotherapy based on high-dose MTX and ARA-C is highly efficient in PCNSL. Response rate and response duration in this series are comparable to the response rates and durations reported after combined radiotherapy and chemotherapy. Neurotoxicity was infrequent.     

原发性中枢神经系统淋巴瘤诊断与治疗进展

原发性中枢神经系统淋巴瘤（primary central nervous system lymphoma,PCNSL）,是一类发生于中枢神经系统恶性非霍奇金淋巴瘤．尽管近年来恶性淋巴瘤的治疗迅速发展．但PCNSL的预后是各种类型淋巴瘤中最差的．5年生存率约20％～30％。放射治疗长期以来被作为PCNSL的标准方案．但是因为其较高的局部复发率和毒副作用限制放射治疗的作用。各种以大剂量甲氨蝶呤为基础新的治疗方案．改善了PCNSL的治疗效果,但是仍然需要更多临床试验的证据来确定最佳治疗方案．     

原发性中枢神经系统淋巴瘤的诊断和治疗

原发性中枢神经系统淋巴瘤(PCNSL)是一种较罕见的中枢神经系统恶性肿瘤,其生物学行为具有侵袭性,临床无典型性,病理形态存在异质性,影像表现多样性,依靠病理免疫组织化学及分子生物学方可确诊.各种以大剂量甲氨蝶呤为基础的治疗方案,改善了PCNSL的治疗效果,并成为PCNSL的标准治疗措施,患者的生存率较单用放疗得以显著地提高.早期诊断并进行有效的综合治疗是延长PCNSL患者生存期和改善生活质量的关键.     

Treatment of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare neoplasm that has captured popular attention because of its rising incidence and marked chemosensitivity. It is a non-Hodgkins B-cell lymphoma (NHL) that appears confined to the central nervous system (CNS) at presentation but may be multifocal within the brain or involve the leptomeninges or eyes at diagnosis. Like systemic lymphoma, it is highly sensitive to corticosteroids, and administration of steroids should be withheld until the diagnosis has been confirmed histologically. Currently, the initial treatment of choice incorporates high-dose methotrexate (HD-MTX) either as a single agent or in combination with other systemic chemotherapies. Whole-brain radiotherapy (WBRT) can be a highly effective treatment modality when combined with MTX, but the combination causes an unacceptably high incidence of severe permanent neurotoxicity, particularly in patients over age 60. Therefore, chemotherapy alone is the initial treatment of choice in older patients. This approach is also being explored in younger patients, but it is possible that deferring radiotherapy may compromise disease control. Consequently, the role of radiotherapy remains to be clarified in newly diagnosed younger patients with PCNSL.     

Chemo-radiotherapy for malignant brain tumors

I) Malignant gliomas: Randomized clinical trials conducted in the USA showed that radiotherapy plus chemotherapy with nitrosoureas offered a long-term survival advantage to patients younger than 60 years old with malignant gliomas. Combination chemotherapy, such as procarbazine/CCNU/vincristine (PCV) must be tested further, and intra-arterial chemotherapy with nitrosoureas offered no survival advantage. Combination chemotherapy with PCV showed efficacy for patients with anaplastic oligodendroglioma and anaplastic oligoastrocytoma. II) Medulloblastoma: The addition of chemotherapy to radiotherapy improved the survival of patients with poor risk medulloblastoma, and may reduce the required craniospinal radiation dose in patients with good risk medulloblastoma. III) Primary CNS lymphoma (PCNSL): Combination of chemotherapy with high-dose MTX and radiotherapy improved survival of patients with PCNSL; however, the neurotoxicity produced by this treatment modality is a serious problem in older patients. IV) Intracranial germ cell tumors: The addition of chemotherapy to radiotherapy may produce long term survival with good quality of life in patients with germinoma. Neoadjuvant therapy consisting of chemotherapy and radiotherapy followed by complete surgical excision improved survival of patients with intracranial nongerminomatous germ cell tumors.     

Clinical response following adjuvant Temozolomide in a patient with primary cerebral lymphoma

A 69-year-old female patient was treated for primary CNS-lymphoma (PCNSL) starting from August 2002. As her general condition allowed no high-dose methotrexate (MTX) therapy, radiotherapy was administered as a first-line treatment. CSF involvement could be managed by intrathecal Ara-C. Her general condition and cognitive status stabilized, but did not improve for 3 months. Therefore, oral chemotherapy with Temozolomide 200 mg/m2 was initiated. After two courses, which were tolerated without any problems, the patient's Karnofsky performance index had improved from 40% to 50%, the Mini-Mental Status rose from 16 to 27/30. The CSF-cell count was elevated again to 23 cells/l without signs of meningeal relapse. Unfortunately, the patient died unexpectedly from suspected pulmonary embolism. We conclude that adjuvant Temozolomide chemotherapy can improve the general condition and cognition in patients with PCNSL even when the general condition is poor. Long-term effects and neurotoxicity remain to be analysed in prospective trials, as well as the efficacy in leptomeningeal disease.     

High-dose methotrexate for elderly patients with primary CNS lymphoma

The introduction of methotrexate (MTX)-based chemotherapy has improved median survival for patients with primary CNS lymphoma (PCNSL). Older age is a negative prognostic marker in patients with PCNSL and may increase the likelihood of MTX toxicity. We studied the response and adverse effects of intravenous high-dose MTX in patients who were 70 or more years of age at the time of diagnosis. We identified 31 patients at our institution diagnosed with PCNSL at age > or =70 years (median, 74 years) who were treated with high-dose MTX (3.5-8 g/m(2)) as initial therapy from 1992 through 2006. The best response to MTX was determined by contrast-enhanced MRI. Toxicity was analyzed by chart review. These 31 patients received a total of 303 cycles of MTX (median, eight cycles per patient). Overall, 87.9% of the cycles required dose reduction because of impaired creatinine clearance. In 30 evaluable patients, the overall radiographic response rate was 96.7%, with 18 complete responses (60%) and 11 partial responses (36.7%). Progression-free survival and overall survival were 7.1 months and 37 months, respectively. Grade I-IV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58% (3.2% grade III), hematological complications in 80.6% (6.5% grade III), and renal toxicity in 29% (0% grade III/IV). High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL.