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Neuro-oncology Mar 2023Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately...
A phase I/II study of intrathecal trastuzumab in human epidermal growth factor receptor 2-positive (HER2-positive) cancer with leptomeningeal metastases: Safety, efficacy, and cerebrospinal fluid pharmacokinetics.
BACKGROUND
Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately systemic trastuzumab which targets the HER2 receptor has little CNS penetration. The purpose of this study was to determine the maximum-tolerated dose of intrathecal trastuzumab and its efficacy in patients with HER2-positive leptomeningeal disease (LMD).
METHODS
This multicenter study enrolled 34 LMD patients in a combined phase I/II study in treating patients with intrathecal trastuzumab. Any HER2-positive histology was allowed in the phase I; the phase II was limited to HER2-positive breast cancer.
RESULTS
Intrathecal trastuzumab was well-tolerated, with one dose limiting toxicity of grade 4 (arachnoiditis) occurring at the 80 mg twice weekly dose. The recommended phase II dose was 80 mg intrathecally twice weekly. Twenty-six patients at dose level 80 mg were included in evaluation for efficacy: partial response was seen in 5 (19.2%) patients, stable disease was observed in 13 (50.0%), and 8 (30.8%) of the patients had progressive disease. Median overall survival (OS) for phase II dose treated patients was 8.3 months (95% CI 5.2-19.6). The phase II HER2-positive breast cancer patients median OS was 10.5 months (95% CI 5.2-20.9). Pharmacokinetic (PK) studies were limited in the setting of concurrent systemic trastuzumab administration, however, did show stable cerebrospinal fluid (CSF) concentrations with repeated dosing suggest that trastuzumab does not accumulate in the CSF in toxic concentrations.
CONCLUSION
This study suggests promise for potentially improved outcomes of HER-positive LMD patients when treated with intrathecal trastuzumab while remaining safe and well-tolerated for patients.
Topics: Humans; Female; Trastuzumab; Receptor, ErbB-2; Breast Neoplasms; Meningeal Carcinomatosis; Antineoplastic Combined Chemotherapy Protocols
PubMed: 35948282
DOI: 10.1093/neuonc/noac195 -
Neurosurgery Clinics of North America Oct 2020Metastases are the most common intracranial tumors in adults. Lung cancer, melanoma, renal cell carcinoma, and breast cancer are the most common primary tumors that... (Review)
Review
Metastases are the most common intracranial tumors in adults. Lung cancer, melanoma, renal cell carcinoma, and breast cancer are the most common primary tumors that metastasize to the brain. Improved detection of small metastases by MRI, and improved systemic therapy for primary tumors, resulted in increased incidence of brain metastasis. Advances in neuroanesthesia and neurosurgery have significantly improved the safety of surgical resection of brain metastases. Surgical approach and active management have become applicable for many patients. Subsequently, brain metastases diagnosis no longer equals palliative treatment. Moreover, the demand for diagnosing brain masses has increased with its associated challenges.
Topics: Brain; Brain Neoplasms; Humans; Meningeal Carcinomatosis
PubMed: 32921351
DOI: 10.1016/j.nec.2020.06.005 -
World Journal of Surgical Oncology Apr 2018Meningeal carcinomatosis (MC) is characterized by diffuse infiltration of tumor cells in meninges. There is no tumor mass in the brain and parenchyma of the spinal cord....
BACKGROUND
Meningeal carcinomatosis (MC) is characterized by diffuse infiltration of tumor cells in meninges. There is no tumor mass in the brain and parenchyma of the spinal cord. MC is divided into primary and metastatic types. MC cases were previously diagnosed postoperatively or at autopsy. Recent advances in spinal abbreviation cytology and imaging have led to increase in number of reported cases. In this study, we discuss the manifestations of MC patients based on magnetic resonance imaging (MRI) findings, as well as the correlation between the manifestations and pathology.
CASE PRESENTATION
MC was confirmed in all three cases by lumbar puncture and gadopentetate dimeglumine-enhanced magnetic resonance imaging. Due to different primary diseases, the patients had specific imaging manifestations.
CONCLUSION
Enhanced MRI examination is extremely sensitive for detecting abnormalities in meninges, which plays a very important role in the diagnosis of MC. Since meninges of some MC patients cannot be enhanced, the enhanced MRI examination cannot be replaced by conventional cerebrospinal abbreviation examination. Attribute to the diversity of MR contrast agents, which could provide higher lesion conspicuity and enhances lesion detection, there may be some more choices to improve the detection rate of MC patients and prolong their survival lifetime.
Topics: Adult; Contrast Media; Female; Humans; Magnetic Resonance Imaging; Male; Meningeal Carcinomatosis; Meningeal Neoplasms; Middle Aged; Prognosis
PubMed: 29653576
DOI: 10.1186/s12957-018-1376-8 -
Current Opinion in Neurology Dec 2023The incidence of leptomeningeal metastases is increasing in the setting of improved survival from systemic cancers. In more recent years, our understanding of... (Review)
Review
PURPOSE OF REVIEW
The incidence of leptomeningeal metastases is increasing in the setting of improved survival from systemic cancers. In more recent years, our understanding of leptomeningeal metastasis pathogenesis, how to diagnose and treat has been evolving.
RECENT FINDINGS
Diagnosing leptomeningeal metastasis has been challenging due to the limitations of cytology and neuroimaging; However, newer techniques detecting circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) have shown potential advantage with diagnosis, quantification and detection of oncogenic mutations. The use of small molecule inhibitors and immunotherapy has shown some promise in specific leptomeningeal metastasis subtypes.
SUMMARY
These new discoveries have improved clinical trials' ability to assess treatment response and thereby more optimally compare different treatments. Furthermore, they have helped the individual clinician better diagnose, monitor the disease and provide novel therapies.
Topics: Humans; Meningeal Carcinomatosis; Neoplasms; Immunotherapy
PubMed: 37865856
DOI: 10.1097/WCO.0000000000001218 -
Chinese Clinical Oncology Jun 2015Leptomeningeal dissemination of tumor cells, also referred to as neoplastic meningitis, is most frequently seen in patients with late-stage cancer and mostly associated... (Review)
Review
Leptomeningeal dissemination of tumor cells, also referred to as neoplastic meningitis, is most frequently seen in patients with late-stage cancer and mostly associated with a poor prognosis. Basically, neoplastic meningitis may affect all patients with a malignant tumor but is most common in patients affected by lung cancer, breast carcinoma, melanoma or hematologic neoplasms such as lymphoma and leukemia. Controlled clinical trials are largely lacking which results in various non-standardized treatment regimens. The presence of solid tumor manifestations in the CNS as well as the extracranial tumor load defines the most appropriate treatment approach. Radiation therapy, systemic chemotherapy and intrathecal treatment must be considered. For each patient, the individual situation needs to be carefully evaluated to determine the potential benefit as well as putative side effects associated with any therapy. A moderate survival benefit and particularly relief from pain and neurological deficits are the main treatment goals. Here, we summarize the management of patients with neoplastic meningitis and review the available treatment options.
Topics: Animals; Combined Modality Therapy; Humans; Meningeal Carcinomatosis; Meningitis; Neuroimaging; Patient Selection; Predictive Value of Tests; Risk Factors; Treatment Outcome
PubMed: 26112812
DOI: 10.3978/j.issn.2304-3865.2015.05.02 -
Spinal Cord Sep 2015To summarize the incidence and spectrum of spinal cord-related complications in patients of tuberculous meningitis. (Review)
Review
OBJECTIVES
To summarize the incidence and spectrum of spinal cord-related complications in patients of tuberculous meningitis.
SETTING
Reports from multiple countries were included.
METHODS
An extensive review of the literature, published in English, was carried out using Scopus, PubMed and Google Scholar databases.
RESULTS
Tuberculous meningitis frequently affects the spinal cord and nerve roots. Initial evidence of spinal cord involvement came from post-mortem examination. Subsequent advancement in neuroimaging like conventional lumbar myelography, computed tomographic myelography and gadolinium-enhanced magnetic resonance-myelography have contributed immensely. Spinal involvement manifests in several forms, like tuberculous radiculomyelitis, spinal tuberculoma, myelitis, syringomyelia, vertebral tuberculosis and very rarely spinal tuberculous abscess. Frequently, tuberculous spinal arachnoiditis develops paradoxically. Infrequently, spinal cord involvement may even be asymptomatic. Spinal cord and spinal nerve involvement is demonstrated by diffuse enhancement of cord parenchyma, nerve roots and meninges on contrast-enhanced magnetic resonance imaging. High cerebrospinal fluid protein content is often a risk factor for arachnoiditis. The most important differential diagnosis of tuberculous arachnoiditis is meningeal carcinomatosis. Anti-tuberculosis therapy is the main stay of treatment for tuberculous meningitis. Higher doses of corticosteroids have been found effective. Surgery should be considered only when pathological confirmation is needed or there is significant spinal cord compression. The outcome in these patients has been unpredictable. Some reports observed excellent recovery and some reported unfavorable outcomes after surgical decompression and debridement.
CONCLUSIONS
Tuberculous meningitis is frequently associated with disabling spinal cord and radicular complications. Available treatment options are far from satisfactory.
Topics: Diagnosis, Differential; Humans; Incidence; Spinal Cord; Spinal Cord Injuries; Tuberculosis, Meningeal
PubMed: 25896347
DOI: 10.1038/sc.2015.58 -
Nature Communications Oct 2021Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past...
Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research.
Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Brain Neoplasms; CD8-Positive T-Lymphocytes; CTLA-4 Antigen; Cell-Free Nucleic Acids; Female; Gene Expression Regulation, Neoplastic; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Interferon-gamma; Ipilimumab; Male; Meningeal Carcinomatosis; Meningeal Neoplasms; Middle Aged; Nivolumab; Programmed Cell Death 1 Receptor; Single-Cell Analysis; Survival Analysis; Tumor Microenvironment
PubMed: 34642316
DOI: 10.1038/s41467-021-25860-5 -
CNS Drugs Jan 2023Leptomeningeal metastases represent an aggressive stage of cancer with few durable treatment options. Improved understanding of cancer biology, neoplastic reliance on... (Review)
Review
Leptomeningeal metastases represent an aggressive stage of cancer with few durable treatment options. Improved understanding of cancer biology, neoplastic reliance on oncogenic driver mutations, and complex immune system interactions have resulted in an explosion in cancer-directed therapy in the last two decades to include small molecule inhibitors and immune checkpoint inhibitors. Most of these therapeutics are underexplored in patients with leptomeningeal metastases, limiting extrapolation of extracranial and even intracranial efficacy outcomes to the unique leptomeningeal space. Further confounding our interpretation of drug activity in the leptomeninges is an incomplete understanding of drug penetration through the blood-cerebrospinal fluid barrier of the choroid plexus. Nevertheless, a number of retrospective studies and promising prospective trials provide evidence of leptomeningeal activity of several small molecule and immune checkpoint inhibitors and underscore potential areas of further therapeutic development for patients harboring leptomeningeal disease.
Topics: Humans; Retrospective Studies; Immune Checkpoint Inhibitors; Prospective Studies; Meningeal Carcinomatosis; Blood-Brain Barrier
PubMed: 36474108
DOI: 10.1007/s40263-022-00975-5 -
Cancer Treatment Reviews Jan 2024Clinical data supporting the best therapeutic approach in leptomeningeal disease (LMD; also known as leptomeningeal metastases or leptomeningeal carcinomatosis) are... (Review)
Review
Clinical data supporting the best therapeutic approach in leptomeningeal disease (LMD; also known as leptomeningeal metastases or leptomeningeal carcinomatosis) are lacking. Despite the development of new agents and increasing incidence of central nervous system metastases, patients with LMD are often excluded from clinical trials in breast cancer, with very few conducted specifically in LMD. Consequently, current evidence may not provide an accurate reflection of real-world clinical practice. This review aims to provide further insight into the treatment strategies for patients with breast cancer and LMD. We explore differences between clinical and real-world studies, considering inclusion criteria, levels of evidence for LMD diagnosis, and time between diagnosis of LMD and LMD-specific treatment initiation. Patient prognosis is poor; median overall survival is limited to several months, with approximately 10% of patients alive at 12 months. Efficacy results have been reported for various systemic and intrathecal agents in LMD to date. Systemic therapies under investigation for LMD in breast cancer include tucatinib, trastuzumab deruxtecan, and paclitaxel trevatide; trastuzumab is the main intrathecal agent currently under investigation. Recent trials investigating systemic or intrathecal therapies are typically small, single-arm studies, and most are restricted to patients with human epidermal growth factor receptor 2-positive breast cancer. Moreover, the variability among inclusion criteria and response assessment tools makes the interpretation of results difficult. Large retrospective cohorts with various inclusion criteria and treatment regimens provide some real-world data. However, there remains an urgent need for randomised clinical trials which include patients with LMD across all breast cancer subtypes.
Topics: Humans; Female; Breast Neoplasms; Retrospective Studies; Meningeal Carcinomatosis; Prognosis; Meningeal Neoplasms
PubMed: 38118373
DOI: 10.1016/j.ctrv.2023.102653 -
International Journal of Radiation... Nov 2020
Topics: Brain Neoplasms; Cerebellar Neoplasms; Craniospinal Irradiation; Craniotomy; Humans; Kidney Neoplasms; Medulloblastoma; Meningeal Carcinomatosis; Metaphor; Neoplasm Seeding; Neoplasms; Postoperative Complications; Preoperative Care; Radiotherapy; Recurrence; Terminology as Topic; Treatment Failure; Ventilators, Mechanical; Wilms Tumor
PubMed: 33069355
DOI: 10.1016/j.ijrobp.2020.06.032