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.

Leptomeningeal metastasis from solid tumors.

Central nervous system (CNS) metastasis from systemic cancers can involve the brain parenchyma, leptomeninges (pia, subarachnoid space and arachnoid mater), and dura. Leptomeningeal metastases (LM), also known by different terms including neoplastic meningitis and carcinomatous meningitis, occur in both solid tumors and hematologic malignancies. This review will focus exclusively on LM arising from solid tumors with a goal of providing the reader an understanding of the epidemiology, pathophysiology, clinical presentation, prognostication, current management and future directions.

Breast brain metastases are associated with increased risk of leptomeningeal disease after stereotactic radiosurgery: a systematic review and meta-analysis.

Brain metastases are the most common malignant tumors of the brain. Leptomeningeal dissemination is a late-stage complication of intracranial metastasis and portends an extremely poor prognosis. An increased risk of leptomeningeal disease (LMD) from metastatic breast cancer compared to other cancer types after stereotactic radiosurgery (SRS) has been reported. Validation of this observation has significant public health ramifications. The aim of this study was to determine the consistency of this association in the available literature via formal meta-analysis and systematic review of the literature. Searches of seven electronic databases from inception to August 2019 were conducted following PRISMA guidelines and appropriate selection criteria. Prognostic hazard ratios (HRs) for LMD in breast cancer brain metastases derived from multivariate regression analysis were analyzed using meta-analysis of proportions. Our search strategy identified 8 studies meeting inclusion criteria which provided data on 2555 unique brain metastases patients treated with SRS. The risk of LMD in the setting of breast cancer brain metastasis was significantly greater compared to other histologic cancer types (pooled HR = 2.22; 95% CI 1.69-2.93; P < 0.001). Statistical assessment of small studies bias and heterogeneity were negative. Outcome certainty was low. Breast cancer brain metastases are associated with an increased risk of LMD compared to other cancer types after SRS. The certainty of this outcome will be improved with future prospective studies. Providers should factor this increased susceptibility for LMD in breast cancer brain metastasis to allow for appropriate risk stratification and the development of appropriate surveillance paradigms.

Predictors of leptomeningeal disease following hypofractionated stereotactic radiotherapy for intact and resected brain metastases.

BACKGROUND: The objective was to evaluate the risk and predictors of developing leptomeningeal disease (LMD) in patients with brain metastases treated with 5-fraction hypofractionated stereotactic radiotherapy (HSRT). METHODS: Patients treated with HSRT for intact brain metastases and/or surgical cavities were reviewed from a prospectively maintained database. Radiographic patterns of LMD were classified as focal classical, diffuse classical, focal nodular, and diffuse nodular. RESULTS: HSRT was delivered, most commonly 30 Gy in 5 fractions, to 320 intracranial lesions (57% intact and 43% surgical cavities) in 235 patients. The median follow-up was 13.4 months (range, 0.8 to 60 mo). LMD developed in 19% of patients with a 1-year LMD rate of 12%. From the diagnosis of LMD, the median overall survival (OS) was 3.8 months (range, 2-20.8 mo). The most common LMD pattern was diffuse nodular (44%). No difference in OS was observed between LMD patterns (P = 0.203). Multivariable analysis identified surgical cavities at significantly higher risk of LMD compared with intact lesions (odds ratio [OR] = 2.30, 95% CI: 1.24, 4.29, P = 0.008). For cavities, radiosensitive tumors (OR = 2.35, 95% CI: 1.04, 5.35, P = 0.041) predicted for LMD, while, for intact metastases, patients receiving treatment with targeted agents or immunotherapy (TA/I) were at lower risk (OR = 0.178, 95% CI: 0.04, 0.79, P = 0.023). CONCLUSIONS: Patients who had a brain metastasis resected were at an increased risk of LMD. OS was poor despite treatment of LMD, and no differences in OS based on the pattern of LMD was observed. Treatment with TA/I was observed to be protective against LMD and requires further study.

Breast leptomeningeal disease: a review of current practices and updates on management.

PURPOSE: Leptomeningeal disease (LMD) is an advanced metastatic disease presentation portending a poor prognosis with minimal treatment options. The advent and widespread use of new systemic therapies for metastatic breast cancer has improved systemic disease control and extended survival; however, as patients live longer, the rates of breast cancer LMD are increasing. METHODS: In this review, a group of medical oncologists, radiation oncologists, radiologists, breast surgeons, and neurosurgeons specializing in treatment of breast cancer reviewed the available published literature and compiled a comprehensive review on the current state of breast cancer LMD. RESULTS: We discuss the pathogenesis, epidemiology, diagnosis, treatment options (including systemic, intrathecal, surgical, and radiotherapy treatment modalities), and treatment response evaluation specific to breast cancer patients. Furthermore, we discuss the controversies within this unique clinical setting and identify potential clinical opportunities to improve upon the diagnosis, treatment, and treatment response evaluation in the management of breast LMD. CONCLUSIONS: We recognize the shortcomings in our current understanding of the disease and explore the future role of genomic/molecular disease characterization, technological innovations, and ongoing clinical trials attempting to improve the prognosis for this advanced disease state.

Seizure prevalence, contributing factors, and prognostic factors in patients with leptomeningeal disease.

BACKGROUND: To determine seizure prevalence and contributing factors in patients with leptomeningeal disease (LMD). METHODS: Authors performed a retrospective review of 79 consecutive patients with a diagnosis of LMD. Associations between categorical variables were assessed using Chi-Square tests or Fisher's Exact tests. Survival was plotted with Kaplan Meier curves. Variables with a log-rank p-value of <0.20 were entered into a Cox Proportional Hazard regression analysis. RESULTS: Seizure prevalence in those with and without brain metastases was 22%. Of those who seized, 65% were admitted for this at least once while only one patient required intubation. Primary malignancy, type or route of chemotherapy administration, form of radiation therapy (craniospinal, focal, or whole brain), surgical treatment, location of LMD, and number of brain metastases did not influence seizure development. Only 13% of patients who never had seizures were on a prophylactic AED (anti-epileptic drug). In patients who had brain metastasis, there was no significant difference in prevalence of seizure before versus after LMD diagnosis suggesting that LMD does not significantly increase the risk of seizure compared to brain metastasis alone. A multivariate analysis revealed that while males trended toward inferior survival, only performance status and treatment with systemic chemotherapy showed a significant association with survival. Median survival time of patients after LMD diagnosis was four months. CONCLUSION: The prevalence of seizure in LMD patients is 22%. There were no statistically significant predisposing factors to seizure development. ECOG and use of systemic chemotherapy were found to be significant prognostic factors.

Leptomeningeal metastasis after effective first-generation EGFR TKI treatment of advanced non-small cell lung cancer.

OBJECTIVE: To evaluate the influence of a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) treatment on the clinical features of leptomeningeal metastasis (LM) progression and outcome in advanced non-small cell lung cancer (NSCLC) patients. METHODS: We retrospectively evaluated advanced NSCLC patients receiving effective first-generation EGFR TKI treatment (e.g., treatment > 6 months) at our institution between January 2008 and February 2014. Incidence, time to progression, and treatment outcome of LM were examined. RESULTS: In our cohort, 29/420 patients (6.9%) developed LM. Among the patients harboring L858R or deletion of exon 19 in EGFR, the incidence of LM was 10.7% (21/197) and 3.4% (7/203), respectively (P = 0.006). The median time to LM progression was 16.5 months (95% confidence interval (CI), 11.9-20.8). The median overall survival (OS) after LM diagnosis was 5.2 months (95% CI, 3.2-7.2). In a subgroup analysis, OS was improved in patients with performance status (PS) ≤ 2 vs. PS > 2 (14.2 months vs. 2.3 months, respectively; P < 0.001). OS was also improved among patients who received, rather than did not receive, anti-tumor treatment (6.0 months vs. 1.9 months, respectively; P < 0.001) or whole brain radiotherapy (WBRT) (6.0 months vs. 3.9 months, respectively; P = 0.038). Multivariate analysis indicated that WBRT is a good prognostic factor (P = 0.048), whereas best support care (P = 0.033) and PS > 2 (P = 0.034) were poor prognostic factors. CONCLUSION: A greater incidence of LM was observed in NSCLC patients harboring EGFR mutations after effective EGFR TKI treatment. In particular, the primary mutation, L858R, potentially predicts a higher risk of LM compared with deletion of exon 19. These results highlight the importance of determining mutation status when evaluating the biological behavior of LM in NSCLC patients who positively respond to EGFR TKI treatment.

Risk of leptomeningeal carcinomatosis in patients with brain metastases treated with stereotactic radiosurgery.

There is limited available literature examining factors that predispose patients to the development of LMC after stereotactic radiosurgery (SRS) for brain metastases. We sought to evaluate risk factors that may predispose patients to LMC after SRS treatment in this case-control study of patients with brain metastases who underwent single-fraction SRS between 2011 and 2016. Demographic and clinical information were collected retrospectively for 19 LMC cases and 30 controls out of 413 screened patients with brain metastases. Risk factors of interest were evaluated by univariate and multivariate logistic regression analyses and overall survival rates were evaluated by Kaplan-Meier survival analysis. About 5% of patients with brain metastases treated with SRS developed LMC. Patients with LMC (median 154 days, 95% CI 33-203 days) demonstrated a poorer overall survival than matched controls (median 417 days, 95% CI 121-512 days, p = 0.002). The most common primary tumor histologies  that lead to the development of LMC were non-small cell lung cancer (36.8%), breast cancer (26.3%), and melanoma (21.1%). No association was found between the risk of LMC and the location of the brain lesion or total volume of brain metastases. Prior surgical resection of brain metastases before SRS was associated with a 6.5 times higher odds (95% CI 1.45-29.35, p = 0.01) of developing LMC post-radiosurgery compared to those with no prior resections of brain metastases. Additionally, adjuvant WBRT may help to reduce the risk of LMC and can be considered in decision-making for patients who have had brain metastasectomy.

Leptomeningeal Carcinomatosis in Colorectal Cancer: The Mayo Clinic Experience.

BACKGROUND: Leptomeningeal metastasis (LM) is an uncommon form of metastatic disease in many cancers. There remains a paucity of literature with regard to the course and management of LM in colorectal cancers (CRCs). The aim of this study was to estimate the incidence of LM in patients with CRC seen at our institution over a 15-year period, and to describe the clinical course and outcome of these cases. METHODS: LM in CRC primary cases between 2000 and 2014 were identified in the Mayo Clinic databases. The charts were retrospectively reviewed. RESULTS: Of 17,095 CRC primaries, we identified 10 patients with LM (0.058%) in this 15-year period. Nine cases were included in the analysis. Four had metastatic disease at the time of their initial CRC diagnosis. Median overall survival after CRC diagnosis was 25.7 months (range, 4.7-74.8 months). Median time to diagnosis of LM after CRC diagnosis was 25.3 months (range, 0-68.1 months). All patients had magnetic resonance imaging findings consistent with LM: 3 patients with spinal LM, 5 patients with intracranial LM, and 1 with both. Neurologic symptoms correlated with site of the lesions, with headache, cranial nerve palsy, lower extremity weakness, and gait disturbance among the most frequently reported. However, not all patients had neurologic findings, with LM lesions found incidentally in 2 cases. Seven patients (78%) had palliative radiotherapy for LM. Three patients continued to receive systemic chemotherapy after diagnosis of LM. Median survival after LM diagnosis was 7 weeks (range, 2-39 weeks). CONCLUSIONS: LM is an exceedingly rare development in the natural course of CRC. It confers a poor prognosis with limited treatment options. At our institution, most patients had their disease addressed by palliative means, with many receiving radiotherapy to control their neurologic symptoms. Based on our series, supportive care remains a sensible approach to the management of LM in CRC.

Pilocytic astrocytoma with leptomeningeal spread in a patient with incontinentia pigmenti presenting with unilateral nystagmus.

Incontinentia pigmenti (IP) is a genetic disorder caused by mutations in IKBKG, leading to functional loss of nuclear factor kappa B (NF-ĸB). We report the case of a 6-month-old female child with IP who presented with unilateral nystagmus and was found to have a pilocytic astrocytoma with leptomeningeal spread. Enhanced understanding of the relationship between NF-ĸB, along with its upstream regulators, and tumorigenesis may shed light on whether a subset of patients with IP may be at increased risk for neoplasia.

Postoperative stereotactic radiosurgery for resected brain metastases: A comparison of outcomes for large resection cavities.

PURPOSE: Although historical trials have established the role of surgical resection followed by whole brain irradiation (WBRT) for brain metastases, WBRT has recently been shown to cause significant neurocognitive decline. Many practitioners have employed postoperative stereotactic radiosurgery (SRS) to tumor resection cavities to increase local control without causing significant neurocognitive sequelae. However, studies analyzing outcomes of large brain metastases treated with resection and postoperative SRS are lacking. Here we compare outcomes in patients with large brain metastases >4 cm to those with smaller metastases ≤4 cm treated with surgical resection followed by SRS to the resection cavity. METHODS AND MATERIALS: Consecutive patients with brain metastases treated at our institution with surgical resection and postoperative SRS were retrospectively reviewed. Patients were stratified into ≤4 cm and >4 cm cohorts based on preoperative maximal tumor dimension. Cumulative incidence of local failure, radiation necrosis, and death were analyzed for the 2 cohorts using a competing-risk model, defined as the time from SRS treatment date to the measured event, death, or last follow-up. RESULTS: A total of 117 consecutive cases were identified. Of these patients, 90 (77%) had preoperative tumors ≤4 cm, and 27 (23%) >4 cm in greatest dimension. The only significant baseline difference between the 2 groups was a higher proportion of patients who underwent gross total resection in the ≤4 cm compared with the >4 cm cohort, 76% versus 48%, respectively (P <.01). The 1-year rates of local failure, radiation necrosis, and overall survival for the ≤4 cm and >4 cm cohorts were 12.3% and 16.0%, 26.9% and 28.4%, and 80.6% and 67.6%, respectively (all P >.05). The rates of local failure and radiation necrosis were not statistically different on multivariable analysis based on tumor size. CONCLUSIONS: Brain metastases >4 cm in largest dimension managed by resection and radiosurgery to the tumor cavity have promising local control rates without a significant increase in radiation necrosis on our retrospective review.

Meningeal carcinomatosis underdiagnosis and overestimation: incidence in a large consecutive and unselected population of breast cancer patients.

BACKGROUND: The incidence of meningeal carcinomatosis appears to be higher than in the past due to advances in neuro-imaging diagnostic techniques and improvements in cancer survival. Among solid tumors, breast cancer is the cancer most commonly associated with meningeal carcinomatosis, with an incidence rate of between 0.8 and 16%. Aim of this study has been i) to evaluate the incidence of meningeal carcinomatosis in a continuous breast cancer unselected series treated in a dedicated Breast Unit and ii) to define the clinico-pathological and molecular parameters associated with meningeal carcinomatosis development. METHODS: A retrospective series of 1915 consecutive patients surgically treated for breast cancer between 1998 and 2010 was collected. Clinico-pathological data were recorded from medical charts and pathological reports, including the date of development of symptomatic meningeal carcinomatosis. Meningeal carcinomatosis incidence was determined at both 5- and 10-year follow-ups. RESULTS: Three patients in the first 5 years of follow-up and six patients in 10 years of follow-up developed meningeal carcinomatosis. An incidence rate of 5.44 per 10,000 patients (95% CI: 1.75-16.9) was observed, with a 5-year risk of 0.3%. At 10-year follow up, the rate increased to 7.55 per 10,000 patients (95% CI: 3.39-16.8). In a univariate analysis, young age, tumor size larger than 15 mm, histological grade 3, more than three metastatic lymph nodes, negative estrogen receptor, positive HER2 and high proliferative index were significantly associated with meningeal carcinomatosis development. CONCLUSIONS: In an unselected breast cancer population, meningeal carcinomatosis is a rare event that is associated with adverse prognostic factors. Meningeal carcinomatosis incidence is overestimated when recorded in biased/high-risk selected breast cancer patients and should not be considered to accurately reflect the overall breast cancer population.

Seasonal variability in the incidence of carcinomatous meningitis.

OBJECT: The aim of the study was to investigate whether there are seasonal differences in the occurrence of carcinomatous meningitis (CM), with a greater prevalence of the disease in months with higher temperatures. METHODS: The authors searched the records of all patients with a diagnosis of CM from 1998 until 2013 at the University Hospital of Patras, Greece. The date of hospitalization was extracted for each patient. The cases were divided into 2 categories depending on the time of CM diagnosis. Based on the official data regarding the annual temperature distribution in this region, the authors divided the patients into 2 groups. The first group consisted of cases diagnosed with CM from October 15 to April 15 (cold climate and shorter daytime duration), whereas the second group comprised patients diagnosed between April 15 and October 15 (warm climate and longer daytime duration). RESULTS: Overall, 44 confirmed cases of CM were found. The most common type of malignancy associated with the development of CM was breast cancer (27 patients), while the second most common tumor was lung carcinoma (11 patients). The median interval between the time of initial cancer diagnosis and CM was 4.5 years. Thirty-one patients were diagnosed with CM during the period between April 15 and October 15, while the remaining 13 patients developed CM between October 15 and April 15, a significant difference (p = 0.01). CONCLUSIONS: Significantly more patients developed CM during the warm season of the year. To the authors' knowledge, this is the first study to provide evidence for the potential seasonal variability in CM incidence. However, these results should be validated prospectively in larger cohorts.

Leptomeningeal metastases from genitourinary cancer: the University of Texas MD Anderson Cancer Center experience.

Leptomeningeal metastasis (LM) most commonly arise from breast and lung cancers, and melanoma. Genitourinary cancer (including ovarian, prostate, uterine kidney and bladder) rarely cause LM, with only case reports published. The aims of the study were to describe cases of patients with Genitourinary cancer and Leptomeningeal metastasis, to estimate its prevalence and describe its behavior and outcome. We queried the MD Anderson database for patients with LM and genitourinary cancer between 1978 and 2011. The files of all patients with genitourinary cancer and leptomeningeal disease were retrospectively reviewed. Out of 93960 GU cancer patients treated in MD Anderson (cervix cancer 13,289, ovarian cancer 13,126, bladder cancer 11,834, prostate cancer 41,830, and kidney 13,881), 31 cases (0.03 %) of GU cancer with LM were identified in MD Anderson Cancer Center (MDACC) between 1978 and 2011. Eight patients had bladder cancer, 4 had cervical cancer, 4 had renal cancer, 8 had ovarian cancer and 7 had prostate cancer. Mean age of diagnosis of cancer was 55.9 ± 11.7 (range 20-74). Mean time from primary diagnosis to LM diagnosis was 141.46 ± 244 weeks (range 0.43-409.57). Median survival after LM diagnosis was 15.7 weeks (range 0.85-142.57). The patients presented with multiple signs and symptoms. Although rare-LM should be considered as a complication of GU cancer. Awareness of early neurological signs and symptoms may help the clinician to make an early diagnosis and possibly intervene to prevent neurological deficits.

Epilepsy meets cancer: when, why, and what to do about it?

The lifetime risk of having epileptic seizures is profoundly increased in patients with cancer: about 20% of all patients with systemic cancer may develop brain metastases. These patients and those with primary brain tumours have a lifetime risk of epilepsy of 20-80%. Moreover, exposure to chemotherapy or radiotherapy to the brain, cancer-related metabolic disturbances, stroke, and infection can provoke seizures. The management of epilepsy in patients with cancer includes diagnosis and treatment of the underlying cerebral pathological changes, secondary prophylaxis with antiepileptic drugs, and limiting of the effect of epilepsy and its treatment on the efficacy and tolerability of anticancer treatments, cognitive function, and quality of life. Because of the concern of drug-drug interactions, the pharmacological approach to epilepsy requires a multidisciplinary approach, specifically in a setting of rapidly increasing choices of agents both to treat cancer and cancer-associated epilepsy.

[Intrathecal methotrexate chemotherapy for leptomeningeal carcinomatosis]. / Meningitis carcinomatosa kezelése intrathecalis methotrexat-kemoterápiával.

Lung and breast cancer can give meningeal metastases. Clinical manifestations of leptomeningeal carcinomatosis include all forms of defect of the central nervous system depending on the localization of carcinomatous foci. Diagnosis is based on the detection of carcinomatous cells by the cytological examination of the cerebrospinal fluid. Without treatment the prognosis is limited to only some weeks or months. In case the meningeal carcinomatosis is related to breast cancer, intrathecal methotrexate chemotherapy may allow a significant survival benefit and improve the quality of life in about half of the patients.