Ongoing Protocols for Non-AIDS Primary Central Nervous System Lymphoma

The optimal treatment for primary central nervous system lymphoma (PCNSL) remains undefined. In this paper, we review the main multi-institutional ongoing protocols for PCNSL. Most of the current protocols evaluate the efficacy of combination high-dose methotrexate-based chemotherapy and brain irradiation in phase II studies. Some trials focus on chemotherapy alone as initial treatment, in order to minimize long-term cognitive sequellae. Because old age appears as a major predisposing factor for combined RT and CT neurotoxicity some specific protocols have been proposed to this particular population.     

Advances for the treatment of primary central nervous system lymphoma (review)

Primary central nervous system lymphoma (PCNSL) is a non-Hodgkin's lymphoma arising in the CNS. This review will focus on the recent advances in the treatment of PCNSL. Combined methotrexate-based chemotherapy and radiation therapy is the standard treatment for PCNSL. A median overall survival of 40-60 months is obtained, however, neurotoxicity is a major problem. Preservation of cognitive function appears better after chemotherapy alone, therefore, there are increasing reports that radiotherapy is deferred after chemotherapy. At the moment, the findings of multicenter randomized trials should be awaited to clarify whether deferring radiotherapy in patients responding to chemotherapy allows them to maintain a better quality of life without increasing the risk of local recurrence. The well-designed, multicenter and randomized trials will elucidate the issues, such as best chemotherapy regimen, no brain irradiation in responder and second-line treatment.     

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.     

Diagnosis and management of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non‐Hodgkin lymphoma (NHL) that is confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. The overall prognosis, diagnosis, and management of PCNSL differ from those for other types of NHL. Prompt diagnosis and initiation of treatment are vital for improving clinical outcomes. PCNSL is responsive to radiation therapy; however, whole‐brain radiotherapy (WBRT) inadequately controls the disease when it is used alone, and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High‐dose methotrexate (HD‐MTX)–based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced‐dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined; however, HD‐MTX–based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials are addressing the roles of rituximab and consolidative treatment with ASCT or reduced‐dose WBRT. Despite high tumor response rates with the initial treatment, many patients relapse with a very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on a patient's age, previous treatment and response, performance status, and comorbidities at the time of relapse. This review provides an overview of the clinical features, diagnosis, pathology, and management of PCNSL in immunocompetent patients, and it focuses on recent advances in treatment. Cancer 2017;123:4314‐24 . © 2017 American Cancer Society.     

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。     

Advances in the Therapy of Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin's lymphoma (NHL) confined to the nervous system. The management of PCNSL is quite different from the usual treatment of either primary brain tumors or systemic NHL. First-generation chemotherapy regimens used successfully in systemic NHL are ineffective in PCNSL, in large part due to the existence of the blood-brain barrier. Whole-brain radiation therapy (WBRT) results in high response rates but rapid relapse, and this treatment is associated with delayed neurotoxicity in patients with PCNSL. The addition of methotrexate-based chemotherapy has improved survival and lessened toxicity for this patient population. Fundamental issues that remain unresolved in PCNSL include identification of the optimal chemotherapy regimen for newly diagnosed and relapsed PCNSL, the role of WBRT and intrathecal chemotherapy in the treatment of PCNSL, and the optimal management of intraocular lymphoma. Finally, the optimal clinical study design for this rare disease has yet to be defined and implemented.     

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.     

Have treatment protocols for primary CNS lymphoma advanced in the past 10 years

Introduction: Primary CNS lymphomas (PCNSL) are highly aggressive tumors and optimal treatment is not yet defined. For the last two decades, clinical trials have focused on developing efficient chemotherapy protocols with or without dose-reduced radiation to avoid late cognitive decline after whole brain radiotherapy (WBRT).

Areas covered: This review addresses the question if these substantial developments have led to clinically relevant therapeutic improvement for PCNSL within the last decade.

Expert opinion: The high risk of neurotoxic side effects of WBRT was further substantiated, and in most centers WBRT is omitted from first-line treatment in patients eligible for high-dose systemic methotrexate (HDMTX)-based chemotherapy. Intensified polychemotherapy regimens, particularly high-dose chemotherapy regimens with autologous stem cell transplantation (HD-ASCT), were investigated within prospective multicenter randomized trials and have achieved long-term disease control in a fraction of patients, but no significant progress was made for elderly patients, who are not able to tolerate intensified chemotherapy. Results on the efficacy of rituximab in PCNSL are conflicting; it did not show clinical benefit in a recent large prospective multicenter randomized trial. New substances such as immune-checkpoint inhibitors and targeted molecules are subject to investigation, but have not yet been implemented in clinical routine.     

Diagnosis and treatment of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is an uncommon form of non-Hodgkin’s lymphoma (NHL) that has been increasing in incidence over the past three decades. Unlike systemic extranodal NHL, the response to therapy for PCNSL patients has been somewhat unsatisfactory. However, methotrexate-based chemotherapy and whole-brain radiotherapy have improved the outcome of patients. Unfortunately, treatment-related neurotoxicity is common, especially in the elderly. Although progress has been made in treating PCNSL, there remains no optimal methotrexate dose or frequency. Treatment of recurrence also remains controversial. These important questions have prompted several clinical studies looking at novel ways to intensify chemotherapy and limit neurotoxicity.     

Cognitive functions in primary CNS lymphoma after single or combined modality regimens

The standard treatment for primary CNS lymphoma (PCNSL) involves high-dose methotrexate-based chemotherapy (HD-MTX) alone or in combination with whole brain radiotherapy (WBRT). The combined modality regimen carries a substantial risk for cognitive impairment, and HD-MTX alone has been used more often recently in part to reduce neurotoxicity. In this study, we assessed cognitive functioning and quality of life in PCNSL survivors treated with WBRT + HD-MTX or HD-MTX alone. Fifty PCNSL patients in disease remission underwent a posttreatment baseline neuropsychological evaluation, and a subset of patients completed a follow-up evaluation. Quality of life and extent of white matter disease and atrophy on MRI were assessed. Comparisons according to treatment type after controlling for age and time since treatment completion showed that patients treated with HD-MTX alone had significantly higher scores on tests of selective attention and memory than patients treated with the combined modality regimen. Patients treated with WBRT + HD-MTX had impairments across most cognitive domains, and these were of sufficient severity to interfere with quality of life, as over 50% were not working due to their illness. Patients treated with HD-MTX alone did not meet criteria for cognitive impairment but scored within 1 SD below the normative sample on most tests. Patients with more extensive white matter disease had lower scores on tests of set-shifting and memory. Cognitive dysfunction was more prevalent in PCNSL survivors treated with WBRT + HD-MTX compared with patients treated with HD-MTX alone.     

Primary CNS lymphoma in patients younger than 60: can whole-brain radiotherapy be deferred?

Whole brain radiotherapy (WBRT) has been increasingly omitted as the first treatment of primary central nervous system lymphoma (PCNSL) because of neurotoxicity risks. However, neurotoxicity risks are lower in young (<60 years) patients; deferring WBRT may not be necessary and may compromise disease control. To investigate this question, we report a consecutive series of young (<60 years) PCNSL patients uniformly treated with a response-adjusted approach, with WBRT omitted in patients with chemosensitive disease. Treatment started with induction chemotherapy consisting of methotrexate (3 g/m(2)), CCNU, procarbazine, methylprednisolone and intrathecal methotrexate, cytarabine, and methylprednisolone. Patients achieving complete response (CR) received five additional chemotherapy cycles and no further treatment. Patients with less than CR were treated on an individual basis, typically with WBRT or high-dose chemotherapy (HDC) with stem cell rescue. Sixty-four patients were included (median age: 47; median KPS: 70). Median progression-free survival (PFS) was 12 months; median overall survival (OS) was 63 months (median follow-up: 108 months). Objective response after induction was 87% (CR: 54%; PR: 33%). To date, salvage WBRT has been given to a total of 27 patients and HDC to 29. Neurotoxicity developed in five patients (none in patients treated with chemotherapy only). Deferring WBRT in chemosensitive patients seems to compromise PFS but not OS. Neurotoxicity was reduced but not eliminated, as salvage WBRT was frequently required. HDC and WBRT were effective salvage treatments. As the objective of treatment in this population is a cure, withholding WBRT may not be the best strategy and deserves further investigation. Ongoing studies are investigating whether upfront treatment with HDC can replace WBRT in this setting.     

Therapie von ZNS-Lymphomen

Primary central nervous system lymphoma (PCNSL) differs from nodal lymphoma with similar histological findings, usually diffuse large B-cell lymphoma, by its strong affinity for the central nervous system (CNS), aggressive course and unusual sensitivity to high-dose methotrexate (HDMTX). Thus, primary therapy of PCNSL is currently based on HDMTX but the optimal chemotherapy regimen has not yet been defined due to the rarity of this disease. In younger patients a cure should be the goal and thus intensified chemotherapy protocols should be considered. Whole brain irradiation does not prolong overall survival when used in primary therapy and thus should not be used routinely. Similar to PCNSL the infrequent CNS involvement of a systemic lymphoma, also called secondary CNS lymphoma, has a very poor prognosis. The scarce data suggest a role for HDMTX-based systemic chemotherapy and high-dose chemotherapy followed by stem cell transplantation for outcome improvement. Avoidance of late neurotoxicity is an important goal in the treatment of PCNSL.     

Primary central nervous system lymphoma: biological aspects and controversies in management

INTRODUCTION: This review was produced from the workshop on primary central nervous system lymphoma (PCNSL) at the European Cancer Conference (ECCO 13) in Paris in 2005. It covers the presentation and biological features of the disease (Professor Khe Hoang-Xuan). The role of chemotherapy, including the management of intraocular lymphoma and the use of high dose chemotherapy followed by autologous stem cell transplantation for PCNSL, is discussed (Dr. Andres Ferreri) as well as controversies in the use of whole brain radiotherapy (WBRT) after chemotherapy (Dr. Michele Reni). The topics covered with discussants at the workshop are also summarised. CONCLUSION: The imaging of the brain and the histopathology including detailed immunohistochemistry is of vital importance in making an accurate diagnosis of the disease and understanding the extent of spread of the disease in the CNS. The importance of high dose methotrexate (HDMTX; dose > or = 1g/m(2)), as the most active drug in the treatment of PCNSL, is stressed. The authors recommend that HDMTX alone or in combination with other active chemotherapy agents should be used to treat PCNSL followed by whole brain radiotherapy (WBRT) unless contraindicated because of the advanced age of the patient and existing cognitive impairment. Only published protocols should be used unless the patient is to be offered a trial that has either national or international support. Baseline neuropsychological tests should be carried out before treatment and repeated during and after treatment. The risks of cognitive impairment associated with the disease, with methotrexate - containing chemotherapy and with whole brain radiotherapy should be explained to patients and relatives when obtaining informed consent. Long-term survival, with current treatment regimes, is possible with PCNSL but this appears limited to patients less than 60 years of age at presentation (mostly patients less than 50 years of age).     

Chemotherapy in newly diagnosed primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) accounts for only 3% of brain tumors. It can involve the brain parenchyma, leptomeninges, eyes and the spinal cord. Unlike systemic lymphoma, durable remissions remain uncommon. Although phase III trials in this rare disease are difficult to perform, many phase II trials have attempted to define standards of care. Treatment modalities for patients with newly diagnosed PCNSL include radiation and/or chemotherapy. While the role of radiation therapy for initial management of PCNSL is controversial, clinical trials will attempt to improve the therapeutic index of this modality. Routes of chemotherapy administration include intravenous, intraocular, intraventricular or intra-arterial. Multiple trials have outlined different methotrexate-based chemotherapy regimens and have used local techniques to improve drug delivery. A major challenge in the management of patients with PCNSL remains the delivery of aggressive treatment with preservation of neurocognitive function. Because PCNSL is rare, it is important to perform multicenter clinical trials and to incorporate detailed measurements of long-term toxicities. In this review we focus on different chemotherapeutic approaches for immunocompetent patients with newly diagnosed PCNSL and discuss the role of local drug delivery in addition to systemic therapy. We also address the neurocognitive toxicity of treatment.     

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.     

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。      

Primary CNS Lymphoma: Treatment with Combined Chemotherapy and Radiotherapy

Primary central nervous system lymphoma (PCNSL) is a relatively uncommon primary brain tumor, but it has become the focus of many clinical trials because of its rising incidence and unique sensitivity to systemic chemotherapeutic agents. Radiotherapy can achieve high response rates and remissions in most patients, but survival is usually only 12–18 months because disease recurs. The addition of systemic chemotherapy, particularly intravenous methotrexate, had markedly improved disease control and many patients can achieve a durable remission and occasionally cure of their disease. Conventional systemic lymphoma drug combinations such as cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) are ineffective. High-dose methotrexate is the single most active and important agent in the treatment of this disease. Whether improved disease control can be accomplished by adding other drugs to high-dose methotrexate or whether it is sufficient as a single agent has yet to be answered. High-dose methotrexate combined with cranial irradiation yields a median survival of at least 40 months and five year survival rates of 22%. However, neurotoxicity is substantial in a significant proportion of patients, particularly those over the age of 60 at the time of treatment. As many as 50% of such patients develop severe dementia. This is particularly important in a disease where approximately half of patients above the age of 60 had presentation. Efforts are now being directed towards not only improving disease control but also minimizing late neurotoxicity. Most efforts are currently directed towards using chemotherapy as the sole modality in the treatment of PCNSL, but both an optimal chemotherapy regimen, and the role of radiotherapy remain to be determined.     

原发中枢神经系统淋巴瘤诊疗进展

原发中枢神经系统淋巴瘤是一种少见的中枢神经系统恶性肿瘤,以大剂量甲氨蝶呤为基础方案诱导化疗是目前一线治疗,随后全脑放疗作为巩固治疗.迟发神经认知功能障碍出现,尤其是老年人,使缓解患者是否需要全脑放疗或减量放疗需要进一步明确.利妥昔单抗治疗PCNSL,初步研究表明美罗华可能给患者带来获益,但研究证据水平较低.HDC/ASCT对于治疗复发性或难治性PCNSL虽有疗效但毒副作用较大,临床价值尚存争议.     

Recommendations for the management of malignant gliomas in the elderly

According to epidemiological estimations, the elderly are going to constitute an increasing proportion of patients with gliomas in the near future. Predominantly glioblastoma histology with invariably fatal outcome, disabling comorbidities and presumed low tolerability of radiochemotherapeutic treatments are the main reasons why elderly patients have been under-represented in the majority of neuro-oncological clinical trials conducted so far. Some small retrospective studies have reported that patients with good performance status receiving surgery plus radiotherapy, and sometimes chemotherapy, may achieve a survival comparable with that of younger patients, however, in the absence of randomized studies, the balance of benefits and adverse effects of aggressive treatments remains controversial. Multidisciplinary evaluation of prognostic factors, such as performance status, cognitive functions, tumor operability and burden of comorbidities, appears to be mandatory in order to choose which patients must not be deprived of an integrated treatment with surgery, full-dose radiotherapy and chemotherapy, and which patients may reasonably be given a shorter radiotherapy plan, or even no treatment at all due to the rapidly fatal course of their disease. Peculiar features of malignant gliomas in the elderly and some practical recommendations of management will be presented and discussed in this review.     

Recommendations for the management of malignant gliomas in the elderly

According to epidemiological estimations, the elderly are going to constitute an increasing proportion of patients with gliomas in the near future. Predominantly glioblastoma histology with invariably fatal outcome, disabling comorbidities and presumed low tolerability of radiochemotherapeutic treatments are the main reasons why elderly patients have been under-represented in the majority of neuro-oncological clinical trials conducted so far. Some small retrospective studies have reported that patients with good performance status receiving surgery plus radiotherapy, and sometimes chemotherapy, may achieve a survival comparable with that of younger patients, however, in the absence of randomized studies, the balance of benefits and adverse effects of aggressive treatments remains controversial. Multidisciplinary evaluation of prognostic factors, such as performance status, cognitive functions, tumor operability and burden of comorbidities, appears to be mandatory in order to choose which patients must not be deprived of an integrated treatment with surgery, full-dose radiotherapy and chemotherapy, and which patients may reasonably be given a shorter radiotherapy plan, or even no treatment at all due to the rapidly fatal course of their disease. Peculiar features of malignant gliomas in the elderly and some practical recommendations of management will be presented and discussed in this review.