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Mondia MWL, Hooks RE, Maragkos GA, Smith VL, McCord MR, Donahue JH, Williams ES, Lopes MB, Schiff D, Asthagiri AR. Primary diffuse leptomeningeal glioblastoma: a case report and literature review. J Neurooncol 2025; 172:265-272. [PMID: 39666263 PMCID: PMC11832630 DOI: 10.1007/s11060-024-04908-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 12/06/2024] [Indexed: 12/13/2024]
Abstract
PURPOSE Glioblastoma (GBM) that presents as leptomeningeal disease (LMD) is extremely rare and fatal. Limited data are available regarding incidence, clinical presentation, and management. Prognosis is poor and no treatment is known to improve survival. METHODS AND RESULTS We present a case report of a 72-year-old female who presented with depressed sensorium, ataxia, and myelopathy. Magnetic resonance imaging (MRI) showed diffuse supratentorial and spinal LMD. There was an absence of any detectable and distinct intraparenchymal lesion on neuroaxis imaging. Biopsy of the Sylvian fissure nodule revealed GBM. Steroid therapy was ineffective for symptom relief. She opted for palliative care and expired shortly after diagnosis. CONCLUSION To our knowledge, this is the first reported case of GBM presenting exclusively as LMD without a primary lesion. If systemic imaging techniques do not provide a biopsy target and cerebrospinal fluid (CSF) studies are non-diagnostic, tissue diagnosis from leptomeningeal biopsy is recommended. Palliative chemoradiation or best supportive care are reasonable treatment options.
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Affiliation(s)
- Mark Willy L Mondia
- Division of Neuro-Oncology, Department of Neurology, University of Virginia, 1300, Jefferson Park Avenue West Complex Room 6225, Charlottesville, 22908, VA, USA.
| | - Rebekka E Hooks
- Division of Neuro-Oncology, Department of Neurology, University of Virginia, 1300, Jefferson Park Avenue West Complex Room 6225, Charlottesville, 22908, VA, USA
| | - Georgios A Maragkos
- Department of Neurosurgery, University of Virginia, Charlottesville, VA, USA
| | - Vanessa L Smith
- Department of Pathology, University of Virginia, Charlottesville, VA, USA
| | - Matthew R McCord
- Department of Pathology, University of Virginia, Charlottesville, VA, USA
| | - Joseph H Donahue
- Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA
| | - Eli S Williams
- Department of Pathology, University of Virginia, Charlottesville, VA, USA
| | - M Beatriz Lopes
- Department of Pathology, University of Virginia, Charlottesville, VA, USA
| | - David Schiff
- Division of Neuro-Oncology, Department of Neurology, University of Virginia, 1300, Jefferson Park Avenue West Complex Room 6225, Charlottesville, 22908, VA, USA
| | - Ashok R Asthagiri
- Department of Neurosurgery, University of Virginia, Charlottesville, VA, USA
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Yue Y, Ren Y, Lu C, Jiang N, Wang S, Fu J, Kong M, Zhang G. The research progress on meningeal metastasis in solid tumors. Discov Oncol 2025; 16:254. [PMID: 40019647 PMCID: PMC11871263 DOI: 10.1007/s12672-025-01950-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 11/08/2024] [Indexed: 03/01/2025] Open
Abstract
Meningeal metastasis (MM), particularly Leptomeningeal metastases (LM), represents the advanced stage of solid tumors and poses a significant threat to patients' lives. Moreover, it imposes a substantial burden on society. LM represents the ultimate and most fatal stage of solid tumors, inflicting devastating consequences on patients and imposing a substantial burden on society. The incidence of LM continues to rise annually, emphasizing the urgent need for early recognition and treatment initiation in individuals with LM to significantly extend overall patient survival. Despite rapid advancements in current LM detection and treatment methods, the diagnosis of LM remains constrained by several limitations such as low diagnostic efficiency, the therapeutic outcomes remain suboptimal. Furthermore, there is currently no universally recognized industry standard for LM treatment, further underscoring its status as an unresolved challenge in tumor management. Additionally, progress towards elucidating the mechanisms underlying MM has stagnated. Therefore, this review aims to comprehensively summarize recent research advances pertaining to MM in solid tumors by elucidating its underlying mechanisms, exploring diagnostic and prognostic biomarkers while addressing existing research challenges.
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Affiliation(s)
- Yi Yue
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yuqing Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Chunya Lu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Nan Jiang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Sihui Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Junkai Fu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Mengrui Kong
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Guojun Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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Nguyen A, Nguyen A, Dada OT, Desai PD, Ricci JC, Godbole NB, Pierre K, Lucke-Wold B. Leptomeningeal Metastasis: A Review of the Pathophysiology, Diagnostic Methodology, and Therapeutic Landscape. Curr Oncol 2023; 30:5906-5931. [PMID: 37366925 PMCID: PMC10297027 DOI: 10.3390/curroncol30060442] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/14/2023] [Accepted: 06/16/2023] [Indexed: 06/28/2023] Open
Abstract
The present review aimed to establish an understanding of the pathophysiology of leptomeningeal disease as it relates to late-stage development among different cancer types. For our purposes, the focused metastatic malignancies include breast cancer, lung cancer, melanoma, primary central nervous system tumors, and hematologic cancers (lymphoma, leukemia, and multiple myeloma). Of note, our discussion was limited to cancer-specific leptomeningeal metastases secondary to the aforementioned primary cancers. LMD mechanisms secondary to non-cancerous pathologies, such as infection or inflammation of the leptomeningeal layer, were excluded from our scope of review. Furthermore, we intended to characterize general leptomeningeal disease, including the specific anatomical infiltration process/area, CSF dissemination, manifesting clinical symptoms in patients afflicted with the disease, detection mechanisms, imaging modalities, and treatment therapies (both preclinical and clinical). Of these parameters, leptomeningeal disease across different primary cancers shares several features. Pathophysiology regarding the development of CNS involvement within the mentioned cancer subtypes is similar in nature and progression of disease. Consequently, detection of leptomeningeal disease, regardless of cancer type, employs several of the same techniques. Cerebrospinal fluid analysis in combination with varied imaging (CT, MRI, and PET-CT) has been noted in the current literature as the gold standard in the diagnosis of leptomeningeal metastasis. Treatment options for the disease are both varied and currently in development, given the rarity of these cases. Our review details the differences in leptomeningeal disease as they pertain through the lens of several different cancer subtypes in an effort to highlight the current state of targeted therapy, the potential shortcomings in treatment, and the direction of preclinical and clinical treatments in the future. As there is a lack of comprehensive reviews that seek to characterize leptomeningeal metastasis from various solid and hematologic cancers altogether, the authors intended to highlight not only the overlapping mechanisms but also the distinct patterning of disease detection and progression as a means to uniquely treat each metastasis type. The scarcity of LMD cases poses a barrier to more robust evaluations of this pathology. However, as treatments for primary cancers have improved over time, so has the incidence of LMD. The increase in diagnosed cases only represents a small fraction of LMD-afflicted patients. More often than not, LMD is determined upon autopsy. The motivation behind this review stems from the increased capacity to study LMD in spite of scarcity or poor patient prognosis. In vitro analysis of leptomeningeal cancer cells has allowed researchers to approach this disease at the level of cancer subtypes and markers. We ultimately hope to facilitate the clinical translation of LMD research through our discourse.
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Affiliation(s)
- Andrew Nguyen
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Alexander Nguyen
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | | | - Persis D. Desai
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Jacob C. Ricci
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | | | - Kevin Pierre
- Department of Radiology, University of Florida, Gainesville, FL 32610, USA
| | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32610, USA
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Park YW, Han K, Kim S, Kwon H, Ahn SS, Moon JH, Kim EH, Kim J, Kang SG, Chang JH, Kim SH, Lee SK. Revisiting prognostic factors in glioma with leptomeningeal metastases: a comprehensive analysis of clinical and molecular factors and treatment modalities. J Neurooncol 2023; 162:59-68. [PMID: 36841906 PMCID: PMC10050057 DOI: 10.1007/s11060-022-04233-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 12/30/2022] [Indexed: 02/27/2023]
Abstract
PURPOSE To comprehensively investigate prognostic factors, including clinical and molecular factors and treatment modalities, in adult glioma patients with leptomeningeal metastases (LM). METHODS Total 226 patients with LM (from 2001 to 2021 among 1495 grade 2 to 4 glioma patients, 88.5% of LM patients being IDH-wildtype) with complete information on IDH mutation, 1p/19q codeletion, and MGMT promoter methylation status were enrolled. Predictors of overall survival (OS) of entire patients were determined by time-dependent Cox analysis, including clinical, molecular, and treatment data. Subgroup analyses were performed for patients with LM at initial diagnosis and LM diagnosed at recurrence (herein, initial and recurrent LM). Identical analyses were performed in IDH-wildtype glioblastoma patients. RESULTS Median OS was 17.0 (IQR 9.7-67.1) months, with shorter median OS in initial LM than recurrent LM patients (12.2 vs 20.6 months, P < 0.001). In entire patients, chemotherapy and antiangiogenic therapy were predictors of longer OS, while male sex and initial LM were predictors of shorter OS. In initial LM, higher KPS, chemotherapy, and antiangiogenic therapy were predictors of longer OS, while male sex was a predictor of shorter OS. In recurrent LM, chemotherapy and longer interval between initial glioma and LM diagnoses were predictors of longer OS, while male sex was a predictor of shorter OS. A similar trend was observed in IDH-wildtype glioblastoma. CONCLUSION Active chemotherapy and antiangiogenic therapy demonstrated survival benefit in glioma patients with LM. There is consistent female survival advantage, whereas longer interval between initial glioma diagnosis and LM development suggests longer OS in recurrent LM.
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Affiliation(s)
- Yae Won Park
- Department of Radiology and Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, Korea
| | - Kyunghwa Han
- Department of Radiology and Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, Korea
| | - Sooyon Kim
- Department of Statistics and Data Science, Yonsei University, Seoul, Korea
| | - Hyuk Kwon
- Sea Salvage & Rescue Unit, Naval Special Warfare Flotilla, Gyeryong, Korea
| | - Sung Soo Ahn
- Department of Radiology and Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, Korea.
| | - Ju Hyung Moon
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea
| | - Eui Hyun Kim
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea
| | - Jinna Kim
- Department of Radiology and Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, Korea
| | - Seok-Gu Kang
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Hee Chang
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea
| | - Se Hoon Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Seung-Koo Lee
- Department of Radiology and Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, Korea
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Sachkova A, Khadhraoui E, Goryaynov S, Batalov A, Solozhentseva KD, Pronin I, Mielke D, Rohde V, Abboud T. Meningeosis Neoplastica in Patients with Glioblastoma: Analysis of 36 Cases. World Neurosurg 2023; 170:e159-e169. [PMID: 36332774 DOI: 10.1016/j.wneu.2022.10.102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 10/23/2022] [Accepted: 10/25/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND Meningeosis neoplastica is a rare manifestation of high-grade gliomas and is usually associated with a devastating outcome. The aim of this bicenter series was to investigate the clinical course and outcome of patients with meningiosis neoplastica. METHODS This case series included patients in whom surgery was performed for World Health Organization grade IV primary and secondary glioblastoma (GBM) at the University Medical Center Göttingen, Göttingen, Germany between 2009 and 2021 and Burdenko Institute of Neurosurgery, Moscow, Russia between 2012 and 2018. Inclusion criteria were manifestation of clinical and neuroradiologic signs of leptomeningeal, ependymal, or spinal dissemination of GBM at various time points during the course of the disease. RESULTS Meningeosis neoplastica was found in 36 patients. Nine patients developed spinal metastases and 12 ependymal dissemination and 15 patients had a leptomeningeal manifestation of high-grade glioma. The median age of patients at first diagnosis of primary tumor was 56 years. Typical symptoms were headache, nausea, vomiting, and acute paraplegia. The median overall survival was 11 months and progression-free survival was 8 months. Meningeosis neoplastica developed a median 2 months after the initial tumor diagnosis. Salvage therapies included ventriculoperitoneal shunting, decompression of spinal metastases, and spinal radiation therapy. The median time between meningeosis manifestation and death was 3 months. CONCLUSIONS Meningeosis neoplastica is a rare manifestation of GBM. It has a poor prognosis. The overall survival after the manifestation of meningeosis was barely longer than 3 months. Salvage therapies did not improve the outcome in our patient cohort.
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Affiliation(s)
- Alexandra Sachkova
- Department of Anesthesiology, University Medical Center Göttingen, Göttingen, Germany; Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany
| | - Eya Khadhraoui
- Institute for Diagnostic and Interventional Radiology, University Medical Center Göttingen, Göttingen, Germany
| | - Sergey Goryaynov
- Burdenko Institute of Neurosurgery, Moscow, Russia; Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | | | | | - Igor Pronin
- Burdenko Institute of Neurosurgery, Moscow, Russia
| | - Dorothee Mielke
- Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany
| | - Veit Rohde
- Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany
| | - Tammam Abboud
- Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany.
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Jang C, Cho BK, Hwang SH, Shin HJ, Yoon SH. Leptomeningeal Spread at the Diagnosis of Glioblastoma Multiforme: A Case Report and Literature Review. Brain Tumor Res Treat 2022; 10:183-189. [PMID: 35929116 PMCID: PMC9353161 DOI: 10.14791/btrt.2022.0013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/28/2022] [Accepted: 06/29/2022] [Indexed: 11/20/2022] Open
Abstract
Approximately two-thirds of glioblastoma (GBM) patients progress to leptomeningeal spread (LMS) within two years. While 90% of LMS cases are diagnosed during the progression and/or recurrence of GBM (defined as secondary LMS), LMS presentation at the time of GBM diagnosis (defined as primary LMS) is very rare. 18F-fluorodeoxy glucose positron emission tomography computed tomography (18F-FDG PET/CT) study helps to diagnose the multifocal spread of the malignant primary brain tumor. Our patient was a 31-year-old man with a tumorous lesion located in the right temporal lobe, a wide area of the leptomeninges, and spinal cord (thoracic 5/6, and lumbar 1 level) involvement as a concurrent manifestation. After the removal of the right temporal tumor, the clinical status progressed rapidly, showing signs of increased intracranial pressure and hydrocephalus caused by LMS. He underwent a ventriculoperitoneal shunt a week after craniotomy. During management, progression of cord compression, paraplegia, bone marrow suppression related to radiochemotherapy, intercurrent infections, and persistent ascites due to peritoneal metastasis of the LMS through the shunt system was observed. The patient finally succumbed to the disease nine months after the diagnosis of simultaneous GBM and LMS. The overall survival of primary LMS with GBM in our case was nine months, which is shorter than that of secondary LMS with GBM. The survival period after the diagnosis of LMS did not seem to be significantly different between primary and secondary LMS. To determine the prognostic effect and difference between primary and secondary LMS, further cooperative studies with large-volume data analysis are warranted.
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Affiliation(s)
- Cheolwon Jang
- Department of Neurosurgery, The Armed Forces Capital Hospital, Seongnam, Korea
| | - Byung-Kyu Cho
- Department of Neurosurgery, The Armed Forces Capital Hospital, Seongnam, Korea.
| | - Sung Hwan Hwang
- Department of Neurosurgery, The Armed Forces Capital Hospital, Seongnam, Korea
| | - Hyung Jin Shin
- Department of Neurosurgery, The Armed Forces Capital Hospital, Seongnam, Korea
| | - Sang Hoon Yoon
- Department of Neurosurgery, The Armed Forces Capital Hospital, Seongnam, Korea
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Kang X, Chen F, Yang SB, Wang YL, Qian ZH, Li Y, Lin H, Li P, Peng YC, Wang XM, Li WB. Intrathecal methotrexate in combination with systemic chemotherapy in glioblastoma patients with leptomeningeal dissemination: A retrospective analysis. World J Clin Cases 2022; 10:5595-5605. [PMID: 35979103 PMCID: PMC9258364 DOI: 10.12998/wjcc.v10.i17.5595] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/30/2022] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Glioblastoma (GBM) is one of the most common and aggressive primary malignant brain tumors with severe symptoms and a poor prognosis. Leptomeningeal dissemination (LMD) is a serious complication of GBM that often results in dire outcomes. There is currently no effective treatment.
AIM To estimate the clinical outcomes of combination therapy in GBM patients with LMD
METHODS A retrospective analysis was conducted using data collected from GBM patients diagnosed with LMD from January 2012 to December 2019 at our institution. All these patients had received at least one cycle of a combination therapy consisting of intrathecal methotrexate (MTX) and systemic chemotherapy. Clinical and pathological data were analyzed to explore the outcome of GBM patients with LMD and to determine the most effective treatment.
RESULTS Twenty-six patients were enrolled in this study. The median time from GBM diagnosis to LMD development was 9.3 mo (range: 2-59 mo). The median overall survival of LMD patients from diagnosis to after receiving systemic chemotherapy in combination with intrathecal MTX was 10.5 mo (range: 2-59 mo). In the Cox univariate analysis, gross resection of tumor (P = 0.022), Karnofsky performance status (KPS) > 60 (P = 0.002), and Ommaya reservoir implant (P < 0.001) were correlated with survival. Multivariate analysis showed that KPS > 60 (P = 0.037) and Ommaya reservoir implant (P = 0.014) were positive factors correlated with survival. Myelotoxicity and gastrointestinal reactions were the common toxicities of this combination therapy. According to Common Terminology Criteria of Adverse Events 4.03, most of the patients presented with toxicity less than grade 3.
CONCLUSION Intrathecal MTX administration combined with systemic chemotherapy is a potentially effective treatment for patients with GBM and LMD, with mild treatment-related side effects.
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Affiliation(s)
- Xun Kang
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Feng Chen
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Shou-Bo Yang
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Ya-Li Wang
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Zeng-Hui Qian
- Department of Neurosurgery, Beijing Tiantan Hsopital, Capital Medical University, Beijing 100070, China
| | - Yan Li
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Hao Lin
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Parker Li
- Clinical Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China
| | - Yi-Chen Peng
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Xiao-Min Wang
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Wen-Bin Li
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
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Leptomeningeal disease in glioblastoma: endgame or opportunity? J Neurooncol 2021; 155:107-115. [PMID: 34623599 DOI: 10.1007/s11060-021-03864-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 09/30/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Glioblastoma is an aggressive cancer with a notoriously poor prognosis. Recent advances in treatment have increased overall survival, though this may be accompanied by an increased incidence of leptomeningeal disease (LMD). LMD carries a particularly severe prognosis and remains a late stage manifestation of glioblastoma without satisfactory treatment. The objective of this review is to survey the literature on treatment of LMD in glioblastoma and to more fully characterize the current therapeutic strategies. METHODS The authors performed a systematic review following PRISMA criteria on PubMed and OVID databases. Articles that included adult patients with LMD from glioblastoma were retrieved and reviewed. RESULTS LMD in glioblastoma patients is increasing in incidence, with reports of up to 21%. The overall survival without treatment is alarmingly brief, with patients surviving between 1.6-3.8 months. All studies showed that treatment does improve overall survival significantly, increasing to 11.7 months in one study. However, no one adjuvant or surgical therapy has been shown to improve survival in LMD significantly over another. Direct treatment methods include chemotherapy (standard, anti-angiogenic, intrathecal, immunotherapy), and radiation. Hydrocephalus is a complication in LMD that can be treated with ventriculoperitoneal shunt placement, however treating hydrocephalus and delivering intrathecal chemotherapy is a challenge. CONCLUSION Though evidence remains lacking and there is no consensus, treatments show a trend towards improving survival and should be considered on a case-by-case basis. Further studies are necessary in the pursuit of a standard of care.
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Birzu C, Tran S, Bielle F, Touat M, Mokhtari K, Younan N, Psimaras D, Hoang‐Xuan K, Sanson M, Delattre J, Idbaih A. Leptomeningeal Spread in Glioblastoma: Diagnostic and Therapeutic Challenges. Oncologist 2020; 25:e1763-e1776. [PMID: 33394574 PMCID: PMC7648332 DOI: 10.1634/theoncologist.2020-0258] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/26/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. Leptomeningeal spread (LMS) is a severe complication of GBM, raising diagnostic and therapeutic challenges in clinical routine. METHODS We performed a review of the literature focused on LMS in GBM. MEDLINE and EMBASE databases were queried from 1989 to 2019 for articles describing diagnosis and therapeutic options in GBM LMS, as well as risk factors and pathogenic mechanisms. RESULTS We retrieved 155 articles, including retrospective series, case reports, and early phase clinical trials, as well as preclinical studies. These articles confirmed that LMS in GBM remains (a) a diagnostic challenge with cytological proof of LMS obtained in only 35% of cases and (b) a therapeutic challenge with a median overall survival below 2 months with best supportive care alone. For patients faced with suggestive clinical symptoms, whole neuroaxis magnetic resonance imaging and cerebrospinal fluid analysis are both recommended. Liquid biopsies are under investigation and may help prompt a reliable diagnosis. Based on the literature, a multimodal and personalized therapeutic approach of LMS, including surgery, radiotherapy, systemic cytotoxic chemotherapy, and intrathecal chemotherapies, may provide benefits to selected patients. Interestingly, molecular targeted therapies appear promising in case of actionable molecular target and should be considered. CONCLUSION As the prognosis of glioblastoma is improving over time, LMS becomes a more common complication. Our review highlights the need for translational studies and clinical trials dedicated to this challenging condition in order to improve diagnostic and therapeutic strategies. IMPLICATIONS FOR PRACTICE This review summarizes the diagnostic tools and applied treatments for leptomeningeal spread, a complication of glioblastoma, as well as their outcomes. The importance of exhaustive molecular testing for molecular targeted therapies is discussed. New diagnostic and therapeutic strategies are outlined, and the need for translational studies and clinical trials dedicated to this challenging condition is highlighted.
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Affiliation(s)
- Cristina Birzu
- Sorbonne Université, INSERM, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Assistance Publique–Hôpitaux de Paris (AP‐HP), Hôpitaux Universitaires La Pitié Salpêtrière—Charles Foix Service de Neurologie 2‐MazarinParisFrance
| | - Suzanne Tran
- Sorbonne Université, INSERM, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Assistance Publique–Hôpitaux de Paris (AP‐HP), Hôpitaux Universitaires La Pitié Salpêtrière—Charles Foix Service de Neuropathologie‐EscourolleParisFrance
| | - Franck Bielle
- Sorbonne Université, INSERM, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Assistance Publique–Hôpitaux de Paris (AP‐HP), Hôpitaux Universitaires La Pitié Salpêtrière—Charles Foix Service de Neuropathologie‐EscourolleParisFrance
| | - Mehdi Touat
- Sorbonne Université, INSERM, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Assistance Publique–Hôpitaux de Paris (AP‐HP), Hôpitaux Universitaires La Pitié Salpêtrière—Charles Foix Service de Neurologie 2‐MazarinParisFrance
| | - Karima Mokhtari
- Sorbonne Université, INSERM, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Assistance Publique–Hôpitaux de Paris (AP‐HP), Hôpitaux Universitaires La Pitié Salpêtrière—Charles Foix Service de Neuropathologie‐EscourolleParisFrance
| | - Nadia Younan
- Sorbonne Université, INSERM, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Assistance Publique–Hôpitaux de Paris (AP‐HP), Hôpitaux Universitaires La Pitié Salpêtrière—Charles Foix Service de Neurologie 2‐MazarinParisFrance
| | - Dimitri Psimaras
- Sorbonne Université, INSERM, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Assistance Publique–Hôpitaux de Paris (AP‐HP), Hôpitaux Universitaires La Pitié Salpêtrière—Charles Foix Service de Neurologie 2‐MazarinParisFrance
| | - Khe Hoang‐Xuan
- Sorbonne Université, INSERM, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Assistance Publique–Hôpitaux de Paris (AP‐HP), Hôpitaux Universitaires La Pitié Salpêtrière—Charles Foix Service de Neurologie 2‐MazarinParisFrance
| | - Marc Sanson
- Sorbonne Université, INSERM, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Assistance Publique–Hôpitaux de Paris (AP‐HP), Hôpitaux Universitaires La Pitié Salpêtrière—Charles Foix Service de Neurologie 2‐MazarinParisFrance
| | - Jean‐Yves Delattre
- Sorbonne Université, INSERM, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Assistance Publique–Hôpitaux de Paris (AP‐HP), Hôpitaux Universitaires La Pitié Salpêtrière—Charles Foix Service de Neurologie 2‐MazarinParisFrance
| | - Ahmed Idbaih
- Sorbonne Université, INSERM, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Assistance Publique–Hôpitaux de Paris (AP‐HP), Hôpitaux Universitaires La Pitié Salpêtrière—Charles Foix Service de Neurologie 2‐MazarinParisFrance
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Buszek SM, Chung C. Radiotherapy in Leptomeningeal Disease: A Systematic Review of Randomized and Non-randomized Trials. Front Oncol 2019; 9:1224. [PMID: 31803614 PMCID: PMC6872542 DOI: 10.3389/fonc.2019.01224] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Accepted: 10/25/2019] [Indexed: 01/12/2023] Open
Abstract
Background: Leptomeningeal disease (LMD), also known as neoplastic meningitis, leptomeningeal carcinomatosis, or carcinomatous meningitis, is a rare cancer complication occurring in ~5% of cases and ultimately leads to significant morbidity and mortality. In the modern era, incidence of this condition continues to rise with longer survival of patients with advanced and even metastatic disease due to continued improvements in systemic therapies that are providing prolonged control of distant disease, but with limited effect in the central nervous system (CNS). Typical treatment strategies include optimal systemic therapy for the primary disease, as well as neuroaxis directed therapies, which may include intrathecal chemotherapy (ITC) or radiotherapy (RT). Methods: A systematic review of radiotherapy for LMD was performed. Medline, EMBASE, and Cochrane databases were searched from 1946 to 2018 for clinical trials, retrospective/prospective reviews, and case series with ≥2 human subjects that used radiation therapy techniques in the treatment of LMD. The outcome measures of interest included: characteristics of trial participants, inclusion/exclusion criteria, study type, number of participants, primary cancer histology, type of intervention for LMD, survival results if reported, length of follow up, and study conclusion. Results: Of 547 unique citations, 62 studies met the pre-specified eligibility criteria. These studies included 36 retrospective cohorts, 11 prospective series, 12 case series, and a single citation of guidelines, NCDB analysis, and a randomized control trial. Owing to study heterogeneity, meta-analyses of the endpoint data could not be performed. Conclusions: LMD is a devastating complication of cancer with reported survivals ranging from 2 to 4 months. Based on this systematic review, the recommendation for the treatment of LMD is for multimodality discussion of cases and treatment, including the use of radiotherapy, for LMD. However, with continued advances in systemic therapy as well as imaging advances, the landscape of LMD is evolving rapidly and the role of RT will likely also continue to evolve and advance. There is limited high-quality evidence to guide the optimal use of RT for the treatment of LMD, and there is a great need for prospective, histology specific investigation of the role of radiotherapy for LMD in the era of modern systemic therapies.
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Affiliation(s)
| | - Caroline Chung
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
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Andersen BM, Miranda C, Hatzoglou V, DeAngelis LM, Miller AM. Leptomeningeal metastases in glioma: The Memorial Sloan Kettering Cancer Center experience. Neurology 2019; 92:e2483-e2491. [PMID: 31019097 DOI: 10.1212/wnl.0000000000007529] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 01/24/2019] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE To perform a retrospective analysis examining the incidence and prognosis of glioma patients with leptomeningeal disease (LMD) at Memorial Sloan Kettering Cancer Center over a 15-year period and correlate these findings with clinicopathologic characteristics. METHODS We conducted a retrospective review of glioma patients with LMD at Memorial Sloan Kettering Cancer Center diagnosed from 2001 to 2016. Patients were identified through a keyword search of their electronic medical record and by ICD-9 codes. RESULTS One hundred three patients were identified with disseminated LMD and 85 patients with subependymal spread of disease, 4.7% of all patients with glioma. These cohorts were analyzed separately for time to development of disseminated LMD/subependymal LMD, median overall survival, and survival from LMD diagnosis. Patients were pooled for subsequent analyses (n = 188) because of comparable clinical behavior. LMD was present at glioma diagnosis in 10% of patients. In the remaining 90% of patients diagnosed at recurrence, time to LMD diagnosis, survival after LMD diagnosis, and overall survival varied by original histology. Patients with oligodendroglioma had a median survival of 10.8 (range 1.8-67.7) months, astrocytoma 6.5 (0.1-28.5) months, and glioblastoma 3.8 (0.1-32.6) months after LMD diagnosis. In addition, we found that treatment of LMD was associated with superior performance status and increased survival. CONCLUSION Patients with LMD diagnosed at relapse may not have decreased overall survival as compared to historical controls with parenchymal relapse and may benefit from treatment.
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Affiliation(s)
- Brian M Andersen
- From the Department of Neurology (B.M.A., C.M.), New York Presbyterian/Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center; and Departments of Radiology (V.H.) and Neurology (L.M.D., A.M.M.) Memorial Sloan Kettering Cancer Center, New York, NY
| | - Caroline Miranda
- From the Department of Neurology (B.M.A., C.M.), New York Presbyterian/Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center; and Departments of Radiology (V.H.) and Neurology (L.M.D., A.M.M.) Memorial Sloan Kettering Cancer Center, New York, NY
| | - Vaios Hatzoglou
- From the Department of Neurology (B.M.A., C.M.), New York Presbyterian/Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center; and Departments of Radiology (V.H.) and Neurology (L.M.D., A.M.M.) Memorial Sloan Kettering Cancer Center, New York, NY
| | - Lisa M DeAngelis
- From the Department of Neurology (B.M.A., C.M.), New York Presbyterian/Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center; and Departments of Radiology (V.H.) and Neurology (L.M.D., A.M.M.) Memorial Sloan Kettering Cancer Center, New York, NY
| | - Alexandra M Miller
- From the Department of Neurology (B.M.A., C.M.), New York Presbyterian/Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center; and Departments of Radiology (V.H.) and Neurology (L.M.D., A.M.M.) Memorial Sloan Kettering Cancer Center, New York, NY.
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12
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Supratentorial high-grade astrocytoma with leptomeningeal spread to the fourth ventricle: a lethal dissemination with dismal prognosis. J Neurooncol 2019; 142:253-261. [PMID: 30604394 DOI: 10.1007/s11060-018-03086-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 12/26/2018] [Indexed: 12/12/2022]
Abstract
PURPOSE Leptomeningeal spread to the fourth ventricle (LSFV) from supratentorial high-grade astrocytoma (HGA) is rarely investigated. The incidence and prognostic merit of LSFV were analyzed in this study. METHODS A consecutive cohort of 175 patients with pathologically diagnosed HGA according to the 2016 WHO classification of brain tumors was enrolled. LSFV was defined as radiological occupation in the fourth ventricle at the moment of initial progression. Clinical, radiological, and pathological data were analyzed to explore the difference between HGA patients with and without LSFV. RESULTS There were 18 of 175 (10.3%) HGAs confirmed with LSFV. The difference of survival rate between patients with LSFV or not was significant in both overall survival (OS) (14.5 vs. 24 months, P = 0.0007) and post progression survival (PPS) (6.0 vs. 11.5 months, P = 0.0004), while no significant difference was observed in time to progression (TTP) (8.5 months vs. 9.5 months P = 0.6795). In the Cox multivariate analysis, LSFV was confirmed as an independent prognostic risk factor for OS (HR 2.06, P = 0.010). LSFV was correlated with younger age (P = 0.044), ventricle infringement of primary tumor (P < 0.001) and higher Ki-67 index (P = 0.013) in further analysis, and the latter two have been validated in the Logistic regression analysis (OR 18.16, P = 0.006; OR 4.04, P = 0.012, respectively). CONCLUSION LSFV was indicative of end-stage for supratentorial HGA patients, which shortened patients' PPS and OS instead of TTP. It's never too cautious to alert this lethal event when tumor harbored ventricle infringement and higher Ki-67 index in routine clinical course.
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Thomas AA, Tucker SM, Nelson CJ, Nickerson JP, Durham SR, Homans AC. Anaplastic pleomorphic xanthoastrocytoma with leptomeningeal dissemination responsive to BRAF inhibition and bevacizumab. Pediatr Blood Cancer 2019; 66:e27465. [PMID: 30255633 DOI: 10.1002/pbc.27465] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 08/22/2018] [Accepted: 08/25/2018] [Indexed: 11/07/2022]
Affiliation(s)
- Alissa A Thomas
- Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont
| | - Suzanne M Tucker
- Department of Pathology, University of California San Diego, San Diego, CA
| | - Carl J Nelson
- Department of Radiation Oncology, University of Vermont College of Medicine, Burlington, Vermont
| | - Joshua P Nickerson
- Department of Diagnostic Radiology, Oregon Health and Science University, Portland, OR
| | - Susan R Durham
- Division of Neurosurgery, Department of Surgery, University of Vermont College of Medicine, Burlington, Vermont
| | - Alan C Homans
- Department of Pediatrics, Division of Hematology/Oncology, University of Vermont College of Medicine, Burlington, Vermont
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Baseline multicentric tumors, distant recurrences and leptomeningeal dissemination predict poor survival in patients with recurrent glioblastomas receiving bevacizumab. J Neurooncol 2018; 142:149-159. [DOI: 10.1007/s11060-018-03075-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 12/06/2018] [Indexed: 12/14/2022]
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Abstract
OPINION STATEMENT Treatment options for leptomeningeal metastases are expanding with greater tolerability and efficacy than in the past. Improved knowledge of molecular subtypes of some cancers can guide in choosing more effective therapeutic options; however, physicians should be mindful that these molecular types can be different in the central nervous system compared to the rest of the body. This is particularly true in breast and lung cancer, in which some patients now can live for many months or even years after diagnosis of leptomeningeal metastases. Options for intrathecal therapies are expanding, but physicians should be mindful that this is a passive delivery system that relies on normal CSF flow, so therapies will not penetrate bulky or parenchymal disease sites, especially in the presence of abnormal CSF flow. When chemotherapeutic options are lacking or unsuccessful, focal radiosurgery which can provide symptomatic relief and proton craniospinal radiation remain effective options. Hopefully more formal studies will be conducted in the future to verify which treatments are indeed most effective for particular types of cancer.
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Affiliation(s)
- Jerome J Graber
- Department of Neurology, Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA, 98122-4470, USA.
| | - Santosh Kesari
- Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Pacific Neuroscience Institute, Providence Saint John's Health Center, Santa Monica, CA, 90404, USA.
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Bevacizumab for Patients with Recurrent Multifocal Glioblastomas. Int J Mol Sci 2017; 18:ijms18112469. [PMID: 29156610 PMCID: PMC5713435 DOI: 10.3390/ijms18112469] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 11/15/2017] [Accepted: 11/16/2017] [Indexed: 11/30/2022] Open
Abstract
In patients with glioblastoma, antiangiogenic therapy with bevacizumab (BEV) has been shown to improve progression-free survival (PFS), but not overall survival (OS). Especially in patients with an unusual infiltrative phenotype as seen in multifocal glioblastoma, the use of BEV therapy is still more controversial. Therefore, we prepared a retrospective case series with 16 patients suffering from a multifocal glioblastoma treated with BEV. We compared these patients to a matched control cohort of 16 patients suffering from glioblastoma with a single lesion treated with BEV. The objective of this study was to evaluate whether the course of disease differs in glioblastoma patients with a multifocal disease pattern compared to those with a single lesion only. Patients were treated with BEV monotherapy or BEV in combination with irinotecan or lomustine (CCNU). Response rates and PFS were similar in both groups. There was a trend for an unfavorable OS in the patient group with multifocal glioblastoma, which was expected due to the generally worse prognosis of multifocal glioblastoma. We investigated whether BEV therapy affects the invasive growth pattern as measured by the appearance of new lesions on magnetic resonance imaging (MRI). Under BEV therapy, there was a trend for a lower frequency of new lesions both in multifocal and solitary glioblastoma. Based on these results, BEV therapy at relapse appears to be justified to no lesser extent in multifocal glioblastoma than in solitary glioblastoma.
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