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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 -
Cancer Treatment Reviews Apr 1999Leptomeningeal carcinomatosis occurs in approximately 5% of patients with cancer. This disorder is being diagnosed with increasing frequency as patients live longer and... (Review)
Review
Leptomeningeal carcinomatosis occurs in approximately 5% of patients with cancer. This disorder is being diagnosed with increasing frequency as patients live longer and as neuro-imaging studies improve. The most common cancers to involve the leptomeninges are breast cancer, lung cancer, and melanomas. Tumour cells reach the leptominges by hematogenous spread or by direct extension from pre-existing lesions and are then disseminated throughout the neuroaxis by the flow of the cerebrospinal fluid. Patients present with signs and symptoms from injury to nerves that traverse the subarachnoid space, direct tumour invasion into the brain or spinal cord, alterations in blood supply to the nervous system, obstruction of normal cerebrospinal fluid (CSF) flow pathways, or general interference with brain function. The diagnosis is most commonly made by lumbar puncture although the CSF cytology is persistently negative in about 10% of patients with leptomeningeal carcinomatosis. Radiologic studies may reveal subarachnoid masses, diffuse contrast enhancement of the meninges, or hydrocephalus without a mass lesion. Without treatment, the median survival of patients with this disorder is 4-6 weeks and death occurs from progressive neurologic dysfunction. Early diagnosis and therapy is critical to preserving neurologic function. Radiation therapy to symptomatic sites and disease visible on neuroimaging studies and intrathecal chemotherapy increases the median survival to 3-6 months. The major favorable prognostic factors include excellent performance status, absence of serious fixed neurologic deficits, normal CSF flow scans, and absent or responsive systemic tumour. Aggressive therapy for this disorder is often accompanied by a necrotizing leukoencephalopathy which becomes symptomatic months after treatment with radiation and intrathecal methotrexate. As currently available therapies are toxic and provide limited benefits, novel approaches are being studied. Further information on the mechanisms of neurotoxicity from antineoplastic agents is critical to providing better outcomes for this increasing common complication of cancer.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Carcinoma; Combined Modality Therapy; Diagnosis, Differential; Diagnostic Imaging; Humans; Meningeal Neoplasms; Meningitis
PubMed: 10395835
DOI: 10.1053/ctrv.1999.0119 -
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 2020Leptomeningeal carcinomatosis is a devastating consequence of late-stage cancer, and despite multimodal treatment, remains rapidly fatal. Definitive diagnosis requires... (Review)
Review
Leptomeningeal carcinomatosis is a devastating consequence of late-stage cancer, and despite multimodal treatment, remains rapidly fatal. Definitive diagnosis requires identification of malignant cells in the cerebrospinal fluid (CSF), or frank disease on MRI. Therapy is generally palliative and consists primarily of radiotherapy and/or chemotherapy, which is administered intrathecally or systemically. Immunotherapies and novel experimental therapies have emerged as promising options for decreasing patient morbidity and mortality. In this review, the authors discuss a refined view of the molecular pathophysiology of leptomeningeal carcinomatosis, current approaches to disease management, and emerging therapies.
Topics: Animals; Brain; Disease Models, Animal; Humans; Meningeal Carcinomatosis
PubMed: 32921356
DOI: 10.1016/j.nec.2020.06.010 -
Molecular and Clinical Oncology May 2019A 66-year-old Japanese male patient was referred to Saitama Medical University International Medical Center for treatment of bladder cancer (clinical stage T2 or higher...
A 66-year-old Japanese male patient was referred to Saitama Medical University International Medical Center for treatment of bladder cancer (clinical stage T2 or higher without metastasis), and underwent radical cystectomy with pelvic lymphadenectomy. The histopathological diagnosis was high-grade urothelial carcinoma (pathological stage T2bN2, ly1, v0) and 2 cycles of adjuvant systemic chemotherapy (gemcitabine plus cisplatin) were administered. At 15 months after the operation, mediastinal and lung hilar lymph nodes and multiple bone metastases were identified on computed tomography imaging. After 3 cycles of the previous regimen as salvage systemic chemotherapy, the lymph node metastases had shrunk and the bone metastases were stable; therefore, further chemotherapy was planned. At 26 days after the initiation of the 4th cycle, the patient felt nausea and lower limb weakness. Spinal and brain magnetic resonance imaging with contrast medium revealed diffuse enhancement at the surface of the spinal cord and brain. In addition, abnormal signal intensity in the subarachnoid space was observed on fluid-attenuated inversion recovery imaging; therefore, the patient was diagnosed with meningeal carcinomatosis (MC). Treatment, including whole-brain radiotherapy, was planned for MC; however, the patient's condition rapidly worsened and he succumbed to the disease 14 days after the diagnosis of MC. The definitive diagnosis of MC was confirmed at autopsy.
PubMed: 31007911
DOI: 10.3892/mco.2019.1820 -
Frontiers in Oncology 2022Immunotherapy has now been integrated as a treatment strategy for most patients with non-small cell lung cancer (NSCLC). However, the pivotal clinical trials that... (Review)
Review
Immunotherapy has now been integrated as a treatment strategy for most patients with non-small cell lung cancer (NSCLC). However, the pivotal clinical trials that demonstrated its impressive efficacy often did not include patients with active, untreated brain metastases or leptomeningeal carcinomatosis. Nevertheless, NSCLC is the most common tumor to metastasize to the brain, and patients develop brain and meningeal involvement in approximately 40 and 10% of cases, respectively. Consequently, the appropriate care of these patients is a recurrent clinical concern. Although there are many aspects that would merit further investigation to explain the mechanism of intracranial response to immune checkpoint inhibitors (ICPs), some data suggest that they are able to cross the blood-brain barrier, resulting in local tumor microenvironment modification. This results in a similar clinical benefit in patients with stable, previously treated brain metastases compared to the general population. Despite important limitations, some real-life studies have described that the ICPs' efficacy was maintained also in less selected patients with untreated or symptomatic brain metastases. In contrast, few data are available about patients with leptomeningeal carcinomatosis. Nevertheless, neurological complications due to ICP treatment in patients with brain metastases have to be evaluated and carefully monitored. Despite the fact that limited data are available in the literature, the purpose of this review is to show that the multimodal treatment of these patients with brain metastases and/or leptomeningeal disease should be discussed during tracing of the history of the disease, participating in the local and possibly systemic control of NSCLC.
PubMed: 35494085
DOI: 10.3389/fonc.2022.787080 -
Surgical Case Reports Nov 2020Meningeal carcinomatosis is a very rare metastatic site of gastric cancer and meningeal carcinomatosis without other metastatic sites is much extremely rare. Herein, we...
BACKGROUND
Meningeal carcinomatosis is a very rare metastatic site of gastric cancer and meningeal carcinomatosis without other metastatic sites is much extremely rare. Herein, we report our experience with a very rare case of meningeal carcinomatosis which was difficult to diagnose the recurrence by general systemic examination and was found due to the deafness despite the sustained high tumor markers.
CASE PRESENTATION
A 68-year-old man consulted a hospital with vomiting and hematemesis. Laboratory tests revealed severe anemia. He was referred to our hospital and underwent an emergency gastroscopy, which revealed Borrman type 3 tumor and oozing of blood. Biopsy specimen showed gastric cancer. After several examinations, total gastrectomy was performed and tegafur-gimeracil-oteracil potassium (S-1) was initiated as adjuvant chemotherapy one month after surgery. Tumor marker levels (CEA and CA19-9) remained high for three months after surgery. S-1 was continued while shortening the imaging study follow-up period. Nine months after surgery, he noticed difficulty in hearing with facial paralysis, dizziness, tinnitus, and appetite loss. He was diagnosed with meningeal carcinomatosis and bilateral internal auditory canal metastasis. He died approximately two months later.
CONCLUSION
Meningeal carcinomatosis should be considered if bilateral deafness and vestibulopathy develop after gastrectomy, even if no recurrence is apparent in the abdominal cavity.
PubMed: 33226536
DOI: 10.1186/s40792-020-01018-1 -
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 -
Neuro-oncology Oct 2022
Topics: Diagnostic Imaging; Humans; Meningeal Carcinomatosis
PubMed: 35421226
DOI: 10.1093/neuonc/noac101 -
Frontiers in Neurology 2023The objective of this research is to investigate the clinical application value of cerebrospinal fluid (CSF) cytology and circulating tumor DNA (ctDNA) in lung...
OBJECTIVE
The objective of this research is to investigate the clinical application value of cerebrospinal fluid (CSF) cytology and circulating tumor DNA (ctDNA) in lung adenocarcinoma (LUAD) meningeal metastasis-meningeal carcinomatosis (MC), and to further explore the possible molecular mechanisms and drug treatment targets of LUAD meningeal metastasis by next-generation sequencing (NGS).
METHODS
We retrospectively analyzed LUAD with MC in 52 patients. CSF cytology was carried out using the slide centrifugation precipitation method and May-Grüwald-Giemsa (MGG) staining. Tumor tissue, plasma and CSF ctDNA of some MC patients were detected by NGS.
RESULTS
Of the 52 MC patients, 46 (88.46%) were positive for CSF cytology and 34 (65.38%) were positive for imaging, with statistically significant differences in diagnostic positivity ( < 0.05). In 32 of these patients, CSF cytology, cerebrospinal fluid ctDNA, plasma ctDNA and MRI examination were performed simultaneously, and the positive rates were 84.38, 100, 56.25, and 62.50% respectively, the difference was statistically significant ( < 0.001). Analysis of the NGS profiles of tumor tissues, plasma and CSF of 12 MC patients: the mutated gene with the highest detection rate was epidermal growth factor receptor (EGFR) and the detection rate were 100, 58.33, and 100% respectively in tumor tissues, plasma and CSF, and there were 6 cases of concordance between plasma and tissue EGFR mutation sites, with a concordance rate of 50.00%, and 12 cases of concordance between CSF and tissue EGFR mutation sites, with a concordance rate of 100%. In addition, mutations not found in tissue or plasma were detected in CSF: FH mutation, SETD2 mutation, WT1 mutation, CDKN2A mutation, CDKN2B mutation, and multiple copy number variants (CNV), with the most detected being CDKN2A mutation and MET amplification.
CONCLUSION
CSF cytology is more sensitive than traditional imaging in the diagnosis of meningeal carcinomatosis and has significant advantages in the early screening and diagnosis of MC patients. CSF ctDNA can be used as a complementary diagnostic method to negative results of CSF cytology and MRI, and CSF ctDNA can be used as an important method for liquid biopsy of patients with MC, which has important clinical significance in revealing the possible molecular mechanisms and drug treatment targets of meningeal metastasis of LUAD.
PubMed: 36937524
DOI: 10.3389/fneur.2023.1076310