Leptomeningeal Carcinomatosis from Solid Tumor Malignancies: Treatment Strategies and Biomarkers.

Leptomeningeal metastases/diseases (LMDs) are a late-stage complication of solid tumor or hematologic malignancies. LMD is spread of cancer cells to the layers of the leptomeninges (pia and arachnoid maters) and subarachnoid space seen in 3 to 5% of cancer patients. It is a disseminated disease which carries with it significant neurologic morbidity and mortality. Our understanding of disease pathophysiology is currently lacking; however, advances are being made. As our knowledge of disease pathogenesis has improved, treatment strategies have evolved. Mainstays of treatment such as radiotherapy have changed from involved-field radiotherapy strategies to proton craniospinal irradiation which has demonstrated promising results in recent clinical trials. Systemic treatment strategies have also improved from more traditional chemotherapeutics with limited central nervous system (CNS) penetration to more targeted therapies with better CNS tumor response. Many challenges remain from earlier clinical detection of disease through improvement of active treatment options, but we are getting closer to meaningful treatment.

Leptomeningeal Metastases in Melanoma Patients: An Update on and Future Perspectives for Diagnosis and Treatment.

Leptomeningeal disease (LMD) is a devastating complication of cancer with a particularly poor prognosis. Among solid tumours, malignant melanoma (MM) has one of the highest rates of metastasis to the leptomeninges, with approximately 10-15% of patients with advanced disease developing LMD. Tumour cells that metastasise to the brain have unique properties that allow them to cross the blood-brain barrier, evade the immune system, and survive in the brain microenvironment. Metastatic colonisation is achieved through dynamic communication between metastatic cells and the tumour microenvironment, resulting in a tumour-permissive milieu. Despite advances in treatment options, the incidence of LMD appears to be increasing and current treatment modalities have a limited impact on survival. This review provides an overview of the biology of LMD, diagnosis and current treatment approaches for MM patients with LMD, and an overview of ongoing clinical trials. Despite the still limited efficacy of current therapies, there is hope that emerging treatments will improve the outcomes for patients with LMD.

Leptomeningeal Metastasis: A Review of the Pathophysiology, Diagnostic Methodology, and Therapeutic Landscape.

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.

The role of the neurologist in the diagnosis and treatment of brain metastases and carcinomatous meningitis.

Traditionally, in the past, most of central nervous system metastases from solid tumors were associated with an advanced phase of the disease needing palliation only, while to date they increasingly develop as an early and/or solitary relapse in patients with the systemic disease under control. This review will cover all the aspects of a modern management of brain and leptomeningeal metastases from diagnosis to the different therapeutic options, either local (surgery, stereotactic radiosurgery, whole-brain radiotherapy with hippocampal avoidance) or systemic. Particular emphasis is reserved to the new-targeted drugs, that allow to target specifically driver molecular alterations. These new compounds pose new problems in terms of monitoring efficacy and adverse events, but increasingly they allow improvement of outcome in comparison to historical controls.

Leveraging Molecular and Immune-Based Therapies in Leptomeningeal Metastases.

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.

Leptomeningeal Metastasis from Non-Small Cell Lung Cancer and Current Landscape of Treatments.

Leptomeningeal metastasis (LM), also known as leptomeningeal carcinomatosis (LC), is a devastating complication of metastatic cancer that occurs when neoplastic cells invade the meningeal space. Diagnosis of LM remains challenging given the heterogeneous signs and symptoms at presentation and requires thorough neurological examination, cerebrospinal fluid (CSF) analysis, and MRI of the brain and spine with gadolinium. Detecting neoplastic cells in the CSF is the gold standard for diagnosing leptomeningeal metastases; however, it has low sensitivity and may require multiple CSF samples. New emerging technologies, such as liquid biopsy of CSF, have increased sensitivity and specificity for detecting circulating tumor cells in CSF. The management of LM in patients with NSCLC requires an individualized multidisciplinary approach. Treatment options include surgery for ventricular shunt placement, radiation therapy to bulky or symptomatic disease sites, systemic or intrathecal chemotherapy, molecularly targeted agents, and, more recently, immunotherapy. Targeting actionable mutations in LM from NSCLC, such as EGFR tyrosine kinase inhibitors or anaplastic lymphoma kinase gene rearrangement inhibitors, has shown encouraging results in terms of disease control and survival. Although there are limited data regarding the use of immunotherapy in LM, immunotherapy has produced promising results in several case reports. In this review, we focused on the epidemiology, pathophysiology, clinical presentation, diagnosis, and current treatment strategies, with a special emphasis on novel agents, including targeted therapies and immunotherapy of LM in patients with NSCLC.

Leptomeningeal metastases in non-small cell lung cancer: Diagnosis and treatment.

Leptomeningeal metastasis (LM) is a rare complication of non-small cell lung cancer (NSCLC) with highly mortality. LM will occur once tumor cells spread to the cerebrospinal fluid (CSF) space. Patients may suffer blindness, paralysis, and mental disorders that seriously affect their quality of life. There is a clear unmet need to improve the efficacy of diagnosis and treatment of LM. To better solve this problem, it is helpful to clarify the potential mechanisms of LM. Clinical manifestations, magnetic resonance imaging, and CSF biopsy are the key components in the diagnosis of NSCLC with LM. CSF cytology is insufficient and should be combined with liquid biology. The application of radiotherapy, intrathecal treatment, targeted therapy and immunotherapy provides more options for LM patients. Each treatment has a particular level of efficacy and can be used alone or in combination for individual patients. New technologies in radiotherapy, drug repositioning in intrathecal treatment, and the higher CSF permeability in TKIs have brought new breakthroughs in the treatment of LM. This review focused on clarifying the potential mechanisms, discussing the major clinical challenges, and summarizing recent advances in the diagnosis and treatment of LM from NSCLC. Future research is essential to improve the efficiency of diagnosis, to optimize therapy and to enhance patient prognosis.

Leptomeningeal metastases: the future is now.

Leptomeningeal metastases (LM) constitute an involvement of cancer which is associated with marked morbidity and mortality. The contemporary diagnostic and therapeutic management of LM from solid tumors is reviewed. Therapeutic modalities including systemic therapies, cerebrospinal fluid (CSF)-directed therapies, and radiation therapy are discussed. This is to provide context for how the field of LM management may evolve in the near term. The future directions currently undergoing investigation for diagnostic, response assessment, and therapeutic purposes are highlighted. This is done within the context of the pathophysiology of the disease. Specifically the role of CSF circulating tumor cells and cell free circulating tumor DNA in diagnosis and response assement are reviewed. Novel therapeutic approaches across a range of modalities are discussed. Numerous ongoing studies which have the potential to alter the management of LM are referenced.

A case report of prostate cancer with leptomeningeal metastasis.

BACKGROUND: Prostate cancer is the most prevalent cancer in men. However, leptomeningeal involvement by prostate carcinoma is a rare event. CASE: Here, we report a 69-year-old patient with castration-resistant metastatic prostate cancer who presented with headache and ataxia. Brain MRI revealed a huge invasive interaxial mass at right occipital lobe with diffuse thickening and enhancement of meninges, the arachnoid, and the pia mater, and he was diagnosed with leptomeningeal carcinomatosis. The patient received whole brain radiotherapy. CONCLUSION: Despite the fact that brain and leptomeningeal metastases are not very common in patients with prostate cancer, signs and symptoms of nervous system disorders should be assessed carefully, and consideration of such unusual metastases must be considered.

Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis.

PURPOSE: Cerebrospinal fluid (CSF) cytology is the gold standard diagnostic test for breast cancer leptomeningeal metastasis (BCLM), but has impaired sensitivity, often necessitating repeated lumbar puncture to confirm or refute diagnosis. Further, there is no quantitative response tool to assess response or progression during BCLM treatment. EXPERIMENTAL DESIGN: Facing the challenge of working with small-volume samples and the lack of common recurrent mutations in breast cancers, cell-free DNA was extracted from the CSF and plasma of patients undergoing investigation for BCLM (n = 30). ctDNA fraction was assessed by ultra-low-pass whole genome sequencing (ulpWGS), which does not require prior tumor sequencing. RESULTS: In this proof-of-concept study, ctDNA was detected (fraction ≥0.10) in the CSF of all 24 patients with BCLM+ (median ctDNA fraction, 0.57), regardless of negative cytology or borderline MRI imaging, whereas CSF ctDNA was not detected in the six patients with BCLM- (median ctDNA fraction 0.03, P < 0.0001). Plasma ctDNA was only detected in patients with extracranial disease progression or who had previously received whole brain radiotherapy. ctDNA fraction was highly concordant with mutant allele fraction measured by tumor mutation-specific ddPCR assays (r = 0.852; P < 0.0001). During intrathecal treatment, serial monitoring (n = 12 patients) showed that suppression of CSF ctDNA fraction was associated with longer BCLM survival (P = 0.034), and rising ctDNA fraction was detectable up to 12 weeks before clinical progression. CONCLUSIONS: Measuring ctDNA fraction by ulpWGS is a quantitative marker demonstrating potential for timely and accurate BCLM diagnosis and therapy response monitoring, with the ultimate aim to improve management of this poor-prognosis patient group.

Cerebrospinal fluid diversion for leptomeningeal metastasis: palliative, procedural and oncologic outcomes.

BACKGROUND: Leptomeningeal metastasis (LM) occurs in 3-5% of patients with solid metastatic tumors and often portends a severe prognosis including symptomatic hydrocephalus and intracranial hypertension. Cerebrospinal fluid (CSF) shunting can provide symptomatic relief in this patient subset; however, few studies have examined the role of shunting in the palliation, prognosis and overall oncologic care of these patients. OBJECTIVE: To identify and evaluate risk factors associated with prognosis after CSF diversion and assess surgical, symptomatic and oncologic outcomes in this population. METHODS: A retrospective study was conducted on patients with solid-malignancy LM treated with a shunt at a NCI-designated Comprehensive Cancer Center between 2010 and 2019. RESULTS: One hundred and ninety patients with metastatic LM underwent CSF diversion. Overall survival was 4.14 months from LM diagnosis (95% CI: 3.29-4.70) and 2.43 months (95% CI: 2.01-3.09) from shunting. Karnofsky performance status (KPS) at time of shunting and brain metastases (BrM) number at LM diagnosis demonstrated significant associations with survival (HR = 0.66; 95% CI [0.51-0.86], p = 0.002; HR = 1.40; 95% CI [1.01-1.93] per 10 BrM, p = 0.04, respectively). Eighty-three percent of patients experienced symptomatic relief, and 79% were discharged home or to rehabilitation facilities post-shunting. Post-shunt, 56% of patients received additional systemic therapy or started or completed WBRT. Complications included infection (5%), symptomatic subdural hygroma/hematoma (6.3%), and shunt externalization/removal/repair (8%). Abdominal seeding was not identified. CONCLUSIONS: CSF diversion for LM with hydrocephalus and intracranial hypertension secondary to metastasis can achieve symptomatic relief, hospital discharge, and return to further oncologic therapy, with a complication profile unique to this pathophysiology. However, decision-making in this population must incorporate end-of-life goals of care given limited prognosis.

Effectiveness of Palliative Cerebrospinal Fluid Shunting for Patients With Leptomeningeal Carcinomatosis-related Hydrocephalus.

BACKGROUND/AIM: Leptomeningeal carcinomatosis (LMC) with hydrocephalus is particularly difficult to treat, and its prognosis is extremely poor. The therapeutic outcomes of 14 patients with LMC-associated hydrocephalus who were treated with cerebrospinal fluid shunting are reported. PATIENTS AND METHODS: The study subjects were 14 LMC patients with solid primary cancer who had developed hydrocephalus. RESULTS: Postoperatively, both symptoms and Karnofsky performance status improved in 100% of patients. Postoperative therapy consisted of whole-brain radiotherapy in 4 cases and molecular targeted therapy in 4, with 6 patients not receiving any postoperative treatment. Median overall survival was 3.7 months, with no significant difference between those who underwent postoperative therapy and those who did not. However, two of those who received molecular targeted therapy survived for more than one year. CONCLUSION: Cerebrospinal fluid shunting for LMC-associated hydrocephalus is an effective therapeutic procedure from the palliative viewpoint. Patients for whom molecular targeted therapy is indicated may have better long-term survival.

Detection of Aneuploidy in Cerebrospinal Fluid from Patients with Breast Cancer Can Improve Diagnosis of Leptomeningeal Metastases.

PURPOSE: Detection of leptomeningeal metastasis is hampered by limited sensitivities of currently used techniques: MRI and cytology of cerebrospinal fluid (CSF). Detection of cell-free tumor DNA in CSF has been proposed as a tumor-specific candidate to detect leptomeningeal metastasis at an earlier stage. The aim of this study was to investigate mutation and aneuploidy status in CSF-derived cell-free DNA (cfDNA) of patients with breast cancer with a clinical suspicion of leptomeningeal metastasis. EXPERIMENTAL DESIGN: cfDNA was isolated from stored remnant CSF and analyzed by targeted next-generation sequencing (NGS; n = 30) and the modified fast aneuploidy screening test-sequencing system (mFAST-SeqS; n = 121). The latter method employs selective amplification of long interspaced nuclear elements sequences that are present throughout the genome and allow for fast and cheap detection of aneuploidy. We compared these results with the gold standard to diagnose leptomeningeal metastasis: cytology. RESULTS: Leptomeningeal metastasis was cytology proven in 13 of 121 patients. Low DNA yields resulted in insufficient molecular coverage of NGS for the majority of samples (success rate, 8/30). The mFAST-SeqS method, successful in 112 of 121 (93%) samples, detected genome-wide aneuploidy in 24 patients. Ten of these patients had cytology-proven leptomeningeal metastasis; 8 additional patients were either concurrently diagnosed with central nervous system metastases by radiological means or developed these soon after the lumbar puncture. The remaining six cases were suspected of leptomeningeal metastasis, but could not be confirmed by cytology or imaging. Aneuploidy was associated with development of leptomeningeal metastasis and significantly worse overall survival. CONCLUSIONS: Aneuploidy in CSF-derived cfDNA may provide a promising biomarker to improve timely detection of leptomeningeal metastasis.

[A Case of Carcinomatous Meningitis from Gastric Cancer with Improvement of QOL by Ventriculoperitoneal Shunt].

In cases where carcinomatous meningitis leads to hydrocephalus and increases intracranial pressure, patients present with exacerbated pain and several neurological symptoms. It is reported that multidisciplinary therapy, including radiation therapy, drug therapy, and surgery, is performed for patients with carcinomatous meningitis; however, it is rarely successful. Ventriculoperitoneal shunting(V-P shunt)is a surgical intervention that might relieve the pain temporarily and improve the quality of life. VPS should be taken into consideration in line with patients' and their families' intentions since the overall survival is fairly short.

Complete response of leptomeningeal carcinomatosis secondary to breast cancer.

Leptomeningeal carcinomatosis (LC) is an unmet medical need associated with death in 4-6 weeks without treatment, delayed by 4 months in some patients with favorable prognosis and aggressive multimodal therapy. Unfortunately, most clinical trials excluded patients with LC, and the best management remains unknown. Here we present the first report of a LC secondary to HR positive breast cancer with a complete response to CDK4/6 inhibitors abemaciclib, letrozole and hippocampal-avoidance whole-brain radiotherapy.

Triphasic waves in electroencephalogram as a possible early marker of carcinomatous meningitis: a case report.

RATIONALE: Carcinomatous meningitis is a rare neurological complication. This condition is difficult to diagnose, and misdiagnosis is common because the clinical manifestations are variable. Cerebrospinal fluid (CSF) cytology is the gold standard for diagnosis. Repeated lumbar puncture is required because of the low positive rate. Our case showed triphasic waves (TWs) in an electroencephalogram (EEG) before cancer cells were detected in cytology. We report this case to demonstrate that TWs in EEG may be a prognostic marker in patients with carcinomatous meningitis. PATIENT CONCERNS: A 76-year-old Chinese male displayed incremental headache, nausea, emesis, and intermittent fever for 2 months. A routine scalp EEG showed mild slow background activity. The CSF analysis demonstrated a slight increase in protein, and the white blood cell count was in the normal range. Cytology did not show any atypical cells. Viral meningitis was considered for the first time. DIAGNOSIS: After admission, a long-term EEG was performed because of his fever and mild abnormalities in the routine EEG. The second EEG showed asymmetric TWs in the frontal brain regions. Lung adenocarcinoma was found after systemic investigation. Finally, the patient was diagnosed with carcinomatous meningitis based on repeated CSF cytology. INTERVENTIONS: The patient received systemic chemotherapy in the Department of Oncology. OUTCOMES: The patient was followed up monthly, and he was lost to follow-up in the sixth month after carcinomatous meningitis was diagnosed. LESSONS: It is difficult to make a diagnosis in the early stage of carcinomatous meningitis because the clinical manifestations lack specificity. Repeated lumbar puncture is time consuming and is painful for the patients. In our case, TWs in EEG were detected before cancer cells were found in cytology. EEG should be performed when carcinomatous meningitis is under consideration.

Leptomeningeal Carcinomatosis: Molecular Landscape, Current Management, and Emerging Therapies.

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.

Leptomeningeal metastases arising from gynecological cancers.

BACKGROUND: Most cases of leptomeningeal metastasis (LM) arise from solid tumors, such as breast cancer, lung cancer, or malignant melanoma. LM arising from gynecological cancers are extremely rare. Longer survival owing to recent advances in chemotherapy and other treatments has contributed to the increased frequency of gynecological cancers metastasizing to the central nervous system (CNS). Detailed information regarding LM is scarce; therefore, we conducted a study concerning LM arising from primary gynecological cancers. METHODS: Among 24 patients with CNS metastases from gynecological cancer treated at our hospital between January 2011 and August 2018, those who were eventually diagnosed with LM were included in this retrospective study. RESULTS: Among 24 patients with CNS metastases, five patients (20.8%) were diagnosed with LM. The primary cancer was endometrial in two, cervical in one, and peritoneal in two patients. Of these five patients, three developed LM as a complication 1-11 months after the treatment of brain metastases; one patient had multiple brain metastases diagnosed at the same time as LM, and one had LM alone, without accompanying brain metastases. The median survival after the diagnosis of LM was 23 (12-69) days, while the median survival of 24 patients after the initial diagnosis of CNS metastases was 106 (13-959) days. CONCLUSION: Although LM arising from gynecological cancers is considered rare, identification of LM may be important to predict prognosis and develop new therapeutic strategies.

Management of leptomeningeal metastases in non-small cell lung cancer.

In leptomeningeal metastasis (LM), malignant lung cancer cells reach the sanctuary site of the leptomeningeal space through haematogenous or lymphatic route and thrive in the leptomeninges because of restricted access of chemotherapeutic agents across the blood brain barrier. The incidence of LM is 3%-5% in non-small cell lung cancer (NSCLC) patients; the incidence is higher in patients with anaplastic lymphoma kinase (ALK) gene rearrangement or epidermal growth factor receptor (EGFR) mutations. However, the real-world burden of undiagnosed cases may be higher. LM diagnosis is based on clinical, radiological, and cytological testing. Disease management remains a challenge because of low central nervous system penetration of drugs. The prognosis of NSCLC patients with LM is poor with an overall survival (OS) of 3 months with contemporary treatment and <11 months with novel therapies. Therapy goals in this patient population are to improve or stabilize neurologic status, improve quality of life, and prolong survival while limiting the toxicity of chemotherapeutic regimens. We reviewed therapeutic options for management of LM in NSCLC patients with or without genetic mutations. Radiotherapy, systemic, or intrathecal chemotherapy, and personalized molecularly targeted therapy prolong the OS in patients with LM. Newer third generation EGFR-tyrosine kinase inhibitors have considerable brain penetration property and have been vital in increasing the OS especially in patients with EGFR mutations. Sequential or combination therapy third generation EGFR agents with radiotherapy or chemotherapy might be effective in increasing the quality of life and overall survival.

Palliative approach to leptomeningeal carcinomatosis in oesophagogastric junction cancer.

Leptomeningeal carcinomatosis (LC) is rare in solid tumours, particularly in gastrointestinal cancers. While other treatment strategies remain undefined, inclusion of palliative care is essential due to its very poor prognosis and variable manifestations. We report a case of oesophagogastric junction adenocarcinoma, previously submitted to surgery and chemotherapy, diagnosed with LC and followed in a palliative care unit. Treatment was comanaged with the oncology team and a palliative approach was decided. In this report, we review the literature and evaluate treatment options, with focus on the importance of palliative care and its potential benefits in patients diagnosed with this rare entity.