-
Blood Sep 2022Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphomatous malignancy that affects the brain, spinal cord, leptomeninges, or vitreoretinal space,... (Review)
Review
Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphomatous malignancy that affects the brain, spinal cord, leptomeninges, or vitreoretinal space, without evidence of systemic involvement. The diagnosis of PCNSL requires a high level of suspicion because clinical presentation varies depending upon involved structures. Initiation of treatment is time sensitive for optimal neurologic recovery and disease control. In general, the prognosis of PCNSL has improved significantly over the past few decades, largely as a result of the introduction and widespread use of high-dose methotrexate (MTX) chemotherapy, which is considered the backbone of first-line polychemotherapy treatment. Upon completion of MTX-based treatment, a consolidation strategy is often required to prolong duration of response. Consolidation can consist of radiation, maintenance therapy, nonmyeloablative chemotherapy, or myeloablative treatment followed by autologous stem cell transplant. Unfortunately, even with consolidation, relapse is common, and 5-year survival rates stand at only 30% to 40%. Novel insights into the pathophysiology of PCNSL have identified key mechanisms in tumor pathogenesis, including activation of the B-cell receptor pathway, immune evasion, and a suppressed tumor immune microenvironment. These insights have led to the identification of novel small molecules targeting these aberrant pathways. The Bruton tyrosine kinase inhibitor ibrutinib and immunomodulatory drugs (lenalidomide or pomalidomide) have shown promising clinical response rates for relapsed/refractory PCNSL and are increasingly used for the treatment of recurrent disease. This review provides a discussion of the clinical presentation of PCNSL, the approach to work-up and staging, and an overview of recent advancements in the understanding of the pathophysiology and current treatment strategies for immunocompetent patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Central Nervous System Neoplasms; Humans; Lymphoma, Non-Hodgkin; Methotrexate; Neoplasm Recurrence, Local; Tumor Microenvironment
PubMed: 34699590
DOI: 10.1182/blood.2020008377 -
International Journal of Molecular... Sep 2021Gliomas are the most common central nervous system tumors. New technologies, including genetic research and advanced statistical methods, revolutionize the therapeutic... (Review)
Review
Gliomas are the most common central nervous system tumors. New technologies, including genetic research and advanced statistical methods, revolutionize the therapeutic approach to the patient and reveal new points of treatment options. Moreover, the 2021 World Health Organization Classification of Tumors of the Central Nervous System has fundamentally changed the classification of gliomas and incorporated many molecular biomarkers. Given the rapid progress in neuro-oncology, here we compile the latest research on prognostic and predictive biomarkers in gliomas. In adult patients, mutations are positive prognostic markers and have the greatest prognostic significance. However, deletion, in IDH-mutant astrocytomas, is a marker of the highest malignancy grade. Moreover, the presence of promoter mutations, alterations, or a combination of chromosome 7 gain and 10 loss upgrade IDH-wildtype astrocytoma to glioblastoma. In pediatric patients, alterations are the most important markers which predict the worse outcome. promoter methylation has the greatest clinical significance in predicting responses to temozolomide (TMZ). Conversely, mismatch repair defects cause hypermutation phenotype predicting poor response to TMZ. Finally, we discussed liquid biopsies, which are promising diagnostic, prognostic, and predictive techniques, but further work is needed to implement these novel technologies in clinical practice.
Topics: Animals; Biomarkers, Tumor; Central Nervous System Neoplasms; DNA Methylation; DNA, Neoplasm; Glioma; Humans; Mutation; Neoplasm Proteins; Prognosis; Temozolomide
PubMed: 34638714
DOI: 10.3390/ijms221910373 -
Haematologica Mar 2023Secondary central nervous system (CNS) lymphoma (SCNSL) is defined by the involvement of the CNS, either at the time of initial diagnosis of systemic lymphoma or in the... (Review)
Review
Secondary central nervous system (CNS) lymphoma (SCNSL) is defined by the involvement of the CNS, either at the time of initial diagnosis of systemic lymphoma or in the setting of relapse, and can be either isolated or with synchronous systemic disease. The risk of CNS involvement in patients with diffuse large B-cell lymphoma is approximately 5%; however, certain clinical and biological features have been associated with a risk of up to 15%. There has been growing interest in improving the definition of patients at increased risk of CNS relapse, as well as identifying effective prophylactic strategies to prevent it. SCNSL often occurs within months of the initial diagnosis of lymphoma, suggesting the presence of occult disease at diagnosis in many cases. The differing presentations of SCNSL create the therapeutic challenge of controlling both the systemic disease and the CNS disease, which uniquely requires agents that penetrate the blood-brain barrier. Outcomes are generally poor with a median overall survival of approximately 6 months in retrospective series, particularly in those patients presenting with SCNSL after prior therapy. Prospective studies of intensive chemotherapy regimens containing high-dose methotrexate, followed by hematopoietic stem cell transplantation have shown the most favorable outcomes, especially for patients receiving thiotepa-based conditioning regimens. However, a proportion of patients will not respond to induction therapies or will subsequently relapse, indicating the need for more effective treatment strategies. In this review we focus on the identification of high-risk patients, prophylactic strategies and recent treatment approaches for SCNSL. The incorporation of novel agents in immunochemotherapy deserves further study in prospective trials.
Topics: Humans; Prospective Studies; Retrospective Studies; Neoplasm Recurrence, Local; Central Nervous System Neoplasms; Lymphoma, Large B-Cell, Diffuse; Methotrexate; Central Nervous System; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36384246
DOI: 10.3324/haematol.2022.281457 -
The Lancet. Oncology Jul 2015The management of primary CNS lymphoma is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the very few controlled... (Review)
Review
The management of primary CNS lymphoma is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the very few controlled studies available. In 2013, the European Association of Neuro-Oncology created a multidisciplinary task force to establish evidence-based guidelines for immunocompetent adults with primary CNS lymphoma. In this Review, we present these guidelines, which provide consensus considerations and recommendations for diagnosis, assessment, staging, and treatment of primary CNS lymphoma. Specifically, we address aspects of care related to surgery, systemic and intrathecal chemotherapy, intensive chemotherapy with autologous stem-cell transplantation, radiotherapy, intraocular manifestations, and management of elderly patients. The guidelines should aid clinicians in their daily practice and decision making, and serve as a basis for future investigations in neuro-oncology.
Topics: Central Nervous System Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Europe; Evidence-Based Medicine; Female; Humans; Immunocompetence; Lymphoma; Male; Neoplasm Invasiveness; Neoplasm Staging; Neurosurgical Procedures; Practice Guidelines as Topic; Prognosis; Radiotherapy, Adjuvant; Societies, Medical; Stem Cell Transplantation; Survival Analysis; Transplantation, Autologous
PubMed: 26149884
DOI: 10.1016/S1470-2045(15)00076-5 -
Journal of Neuro-oncology Nov 2022Meningiomas are the most common primary central nervous system neoplasm. Despite promising recent progress in elucidating the genomic landscape and underlying biology of... (Review)
Review
Meningiomas are the most common primary central nervous system neoplasm. Despite promising recent progress in elucidating the genomic landscape and underlying biology of these histologically, molecularly, and clinically diverse tumors, the mainstays of meningioma treatment remain maximal safe resection and radiation therapy. The aim of this review of meningioma radiotherapy is to provide a concise summary of the history, current evidence, and future for application of radiotherapy in meningioma treatment.
Topics: Humans; Meningioma; Meningeal Neoplasms; Radiotherapy, Adjuvant
PubMed: 36315366
DOI: 10.1007/s11060-022-04171-9 -
Blood Apr 2022Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse,...
Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Cyclophosphamide; Doxorubicin; Humans; Lymphoma, Large B-Cell, Diffuse; Methotrexate; Neoplasm Recurrence, Local; Prednisone; Retrospective Studies; Rituximab; Vincristine
PubMed: 34995350
DOI: 10.1182/blood.2021014506 -
Hematology. American Society of... Dec 2022The prevention of central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) continues to be one of the most contentious areas of lymphoma management.... (Review)
Review
The prevention of central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) continues to be one of the most contentious areas of lymphoma management. Outcomes for patients with secondary CNS lymphoma (SCNSL) have historically been very poor. However, in recent years improved responses have been reported with intensive immunochemotherapy approaches, and there is a growing interest in potential novel/cellular therapies. Traditional methods for selecting patients for CNS prophylaxis, including the CNS International Prognostic Index, are hampered by a lack of specificity, and there is accumulating evidence to question the efficacy of widely employed prophylactic interventions, including intrathecal and high-dose methotrexate (HD-MTX). Given the potential toxicity of HD-MTX in particular and the ongoing need to prioritize systemic disease control in high-risk patients, there is an urgent need to develop more robust methods for identifying patients at highest risk of CNS relapse, as well as investigating prophylactic interventions with greater efficacy. Here we review new evidence in this field from the last 5 years, focusing on the potential use of molecular diagnostics to improve the identification of high-risk patients, recent large data sets questioning the efficacy of HD-MTX, and the current approach to management of patients with SCNSL. We provide a suggested algorithm for approaching this very challenging clinical scenario.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Lymphoma, Large B-Cell, Diffuse; Central Nervous System Neoplasms; Methotrexate; Rituximab
PubMed: 36485105
DOI: 10.1182/hematology.2022000331 -
The Lancet. Neurology Apr 2019Brain and CNS cancers (collectively referred to as CNS cancers) are a source of mortality and morbidity for which diagnosis and treatment require extensive resource...
BACKGROUND
Brain and CNS cancers (collectively referred to as CNS cancers) are a source of mortality and morbidity for which diagnosis and treatment require extensive resource allocation and sophisticated diagnostic and therapeutic technology. Previous epidemiological studies are limited to specific geographical regions or time periods, making them difficult to compare on a global scale. In this analysis, we aimed to provide a comparable and comprehensive estimation of the global burden of brain cancer between 1990 and 2016.
METHODS
We report means and 95% uncertainty intervals (UIs) for incidence, mortality, and disability-adjusted life-years (DALYs) estimates for CNS cancers (according to the International Classification of Diseases tenth revision: malignant neoplasm of meninges, malignant neoplasm of brain, and malignant neoplasm of spinal cord, cranial nerves, and other parts of CNS) from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016. Data sources include vital registration and cancer registry data. Mortality was modelled using an ensemble model approach. Incidence was estimated by dividing the final mortality estimates by mortality to incidence ratios. DALYs were estimated by summing years of life lost and years lived with disability. Locations were grouped into quintiles based on the Socio-demographic Index (SDI), a summary indicator of income per capita, years of schooling, and total fertility rate.
FINDINGS
In 2016, there were 330 000 (95% UI 299 000 to 349 000) incident cases of CNS cancer and 227 000 (205 000 to 241 000) deaths globally, and age-standardised incidence rates of CNS cancer increased globally by 17·3% (95% UI 11·4 to 26·9) between 1990 and 2016 (2016 age-standardised incidence rate 4·63 per 100 000 person-years [4·17 to 4·90]). The highest age-standardised incidence rate was in the highest quintile of SDI (6·91 [5·71 to 7·53]). Age-standardised incidence rates increased with each SDI quintile. East Asia was the region with the most incident cases of CNS cancer for both sexes in 2016 (108 000 [95% UI 98 000 to 122 000]), followed by western Europe (49 000 [37 000 to 54 000]), and south Asia (31 000 [29 000 to 37 000]). The top three countries with the highest number of incident cases were China, the USA, and India. CNS cancer was responsible for 7·7 million (95% UI 6·9 to 8·3) DALYs globally, a non-significant change in age-standardised DALY rate of -10·0% (-16·4 to 2·6) between 1990 and 2016. The age-standardised DALY rate decreased in the high SDI quintile (-10·0% [-27·1 to -0·1]) and high-middle SDI quintile (-10·5% [-18·4 to -1·4]) over time but increased in the low SDI quintile (22·5% [11·2 to 50·5]).
INTERPRETATION
CNS cancer is responsible for substantial morbidity and mortality worldwide, and incidence increased between 1990 and 2016. Significant geographical and regional variation in the incidence of CNS cancer might be reflective of differences in diagnoses and reporting practices or unknown environmental and genetic risk factors. Future efforts are needed to analyse CNS cancer burden by subtype.
FUNDING
Bill & Melinda Gates Foundation.
Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Brain Neoplasms; Central Nervous System Neoplasms; Child; Child, Preschool; Cost of Illness; Female; Fertility; Global Burden of Disease; Humans; Incidence; Infant; Male; Middle Aged; Prevalence; Risk Factors; Sex Factors; Socioeconomic Factors; Young Adult
PubMed: 30797715
DOI: 10.1016/S1474-4422(18)30468-X -
Continuum (Minneapolis, Minn.) Dec 2020Management of metastasis to the central nervous system (CNS) has evolved, and molecular characterization of metastatic disease is now routinely done. Targeted therapies,... (Review)
Review
PURPOSE OF REVIEW
Management of metastasis to the central nervous system (CNS) has evolved, and molecular characterization of metastatic disease is now routinely done. Targeted therapies, once few in number with limited penetration into the CNS, have multiplied in number and increased in CNS coverage. This article addresses recent advances in the evaluation and clinical management of patients with CNS metastasis.
RECENT FINDINGS
Metastasis of cancer to the CNS can be diagnosed and characterized with novel techniques, including molecular analyses of the spinal fluid, so-called liquid biopsies. Resected parenchymal CNS metastases are now routinely subjected to genomic sequencing. For patients with CNS metastases displaying targetable mutations, a wide variety of treatment options are available, including deferral of radiation therapy in favor of a trial of an orally bioavailable targeted therapy or immunotherapy. For patients without a molecularly targetable lesion, local treatment in the form of radiation therapy, now most often stereotactic radiosurgery, is supplanting untargeted whole-brain radiation therapy.
SUMMARY
Technologic advances in diagnosis and management have resulted in new diagnostic and therapeutic approaches to patients with metastasis to the CNS, with resulting improvements in progression-free and overall survival.
Topics: Brain Neoplasms; Central Nervous System; Central Nervous System Neoplasms; Cranial Irradiation; Humans; Radiosurgery
PubMed: 33273173
DOI: 10.1212/CON.0000000000000939 -
Clinical Cancer Research : An Official... Nov 2014
Topics: Central Nervous System Neoplasms; Humans
PubMed: 25398841
DOI: 10.1158/1078-0432.CCR-14-1258