Incidence Of Leptomeningeal Metastasis Research Articles

Chapter 13 - Leptomeningeal metastasis

Leptomeningeal metastasis (LM) results from dissemination of cancer cells to both the leptomeninges (pia and arachnoid) and cerebrospinal fluid (CSF) compartment. Breast cancer, lung cancer, and melanoma are the most common solid tumors that cause LM. Recent approval of more active anticancer therapies has resulted in improvement in survival that is partly responsible for an increased incidence of LM. Neurologic deficits, once manifest, are mostly irreversible, and often have a significant impact on patient quality of life. LM-directed therapy is based on symptom palliation, circumscribed use of neurosurgery, limited field radiotherapy, intra-CSF and systemic therapies. Novel methods of detecting LM include detection of CSF circulating tumor cells and tumor cell-free DNA. A recent international guideline for a standardization of response assessment in LM may improve cross-trial comparisons as well as within-trial evaluation of treatment. An increasing number of retrospective studies suggest that molecular-targeted therapy, such as EGFR and ALK inhibitors in lung cancer, trastuzumab in HER2+ breast cancer, and BRAF inhibitors in melanoma, may be effective as part of the multidisciplinary management of LM. Prospective randomized trials with standardized response assessment are needed to further validate these preliminary findings.

The role of EGFR-TKI for leptomeningeal metastases from non-small cell lung cancer.

Leptomeningeal metastasis (LM) is a terminal event in the development of non-small cell lung cancer (NSCLC). It has a poor prognosis with median survival of 1.9 months if untreated. The improvement of OS in NSCLC patients relatively increases incidence of LM. While current therapeutic options for LM are limited. Epidermal growth factor receptor-tyrosine kinase inhibitors are a class of small molecules and show dramatic response in epidermal growth factor receptor mutated patients. It also has a distinct therapeutic potential against brain metastases. Although there are some studies on EGFR-TKIs and brain metastases, the role of EGFR-TKIs on LM are not fully clarified. In this review, we will summarize current evidences concerning the use and discuss the role of EGFR-TKIs on LM.

Leptomeningeal carcinomatosis as the primary presentation of relapse in breast cancer.

Leptomeningeal metastasis (LM) is an uncommon presentation of relapse in breast cancer, which is associated with poor clinical outcomes and poor prognosis. Notably, LM most commonly occurs in breast cancer. The aim of the present review was to investigate the occurrence of LM as the primary presentation of relapse following remission in breast cancer patients and to determine whether specific histological subtypes are predisposed to meningeal metastases. In addition, the present review evaluated whether patients presenting with LM as the primary site of relapse exhibit differences in survival when compared with patients exhibiting metastasis to other sites. Cross-sectional studies have demonstrated that LM is commonly associated with other sites of distant metastasis including lung, liver and bone metastases. The histological breast cancer subtype most commonly associated with LM was invasive lobular carcinoma, while triple-negative breast cancer patients appear to be predisposed to the development of LM when considering the overall prevalence of histological breast cancer subtypes. At present, data regarding LM as the primary site of relapse are limited due to its rarity as the first site of metastasis in breast cancer. Case-controlled studies are required to investigate the incidence of LM as the primary site of recurrence in breast cancer patients as this would enable treatment standardization and identification of prognostic factors for improved survival.

Efficacy and Security of Intrathecal with Methotrexate in the Treatment of Meningeal Carcinomatosis

背景与目的脑膜癌病是中枢神经系统转移瘤的一种少见类型。近年来，随着恶性肿瘤治疗疗效的提高，患者生存期延长，脑膜癌病的发病率逐年增加，目前尚缺乏有效的治疗手段。本研究旨在探讨鞘内注射甲氨蝶呤（methotrexate, MTX）治疗脑膜转移的疗效、安全性和预后。方法对27例脑膜转移患者的临床资料、脑脊液实验室检查进行回顾性分析，并分析鞘注化疗后的不良反应及预后。结果27例脑膜转移患者接受鞘注化疗后，70.4%获得临床症状缓解，但脑脊液压力和脑脊液生化改变无统计学差异。55.6%患者无不适，25.9%出现下肢麻木、轻微疼痛，无严重不可逆的不良反应发生。本组患者中位生存期4个月。结论鞘内注射MTX可改善脑膜癌病患者临床症状，无严重不良反应发生。

Leptomeningeal carcinomatosis in colorectal cancer: The Mayo Clinic experience.

710 Background: Leptomeningeal metastasis (LM) has been described as a rare form of metastatic disease progression in colorectal cancer (CRC). There remains a paucity of literature with regards to the course and management of LM in CRC. The aim of this study was to estimate the incidence of LM in CRC patients 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. One patient also had a lung adenocarcinoma diagnosed during initial staging for the CRC primary. Median overall survival after CRC diagnosis was 25.7 months (range 4.7-74.8). Median time to diagnosis of LM after CRC diagnosis was 25.3 months (range 1-68.1). All patients had MRI findings consistent with LM: 3 patients with spinal LM, 5 patients with intracranial LM, 1 with both. One of three CSF analyses at the time of LM workup was positive for malignant cells; all had elevated protein. 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 two cases. Seven patients (78%) had palliative radiotherapy (RT) for LM. Three patients continued to receive systemic chemotherapy after diagnosis of LM. No patients underwent intrathecal chemotherapy. Median survival after LM diagnosis was 7 weeks (range 2-39). Conclusions: The diagnosis of LM is an exceedingly rare development in the natural course of CRC. It continues to confer an extremely poor prognosis with limited treatment options. At our institution, most patients had their disease addressed by palliative means, with many receiving RT to control their neurologic symptoms. Based on our series, supportive care remains a sensible approach to the management of LM in CRC.

O3-9-6 - Molecular Targeting Therapy and Csf Shunt for Patients with Leptomeningeal Metastasis From Lung Adenocarcinoma

Background: The incidence of leptomeningeal metastasis (LM) has increased in patients with lung adenocarcinoma (LAC) because of recent improvements in survival. New effective therapies for lung cancer have underscored the clinical significance of LM. LM associated with hydrocephalus (LM-H) has been particularly hard to be controlled of severe symptom by chemotherapy and/or radiotherapy. We reviewed the outcomes of patients with LAC-LM-H who underwent multidisciplinary treatment (EGFR-TKI or ALK-inhibitor, cerebrospinal fluid (CSF) shunt and/ or radiotherapy) in our institute.Methods: Data of patients with LAC-LM-H diagnosed by MR images and cytological examination were retrospectively analyzed. Seventeen LAC-LM-H patients were treated between June 2008 and November 2013. Patients underwent CSF shunt followed by EGFR-TKI or ALK-inhibitor therapy, if they had EGFR mutant or ALK fusion protein, systemic life expectancy longer than three months after control of their LM, and controlled extra CNS metastases. Overall survival was analysis with Kaplan-Meier survival curves.Results: The patients consisted of 4 men and 13 women with a median age at LM of 59 years (range 39-76). Sixteen patients were administrated EGFR-TKI, and one patient was ALK-inhibitor. Median overall survival (mOS) was 5.5 months from the onset of LM, and 3.5 months after CSF shunt. The longest survivors were alive for 20 months (ALK positive) and 15 months (EGFR mutant). Median OS in patients of ECOG performance status 1-2 significantly longer than those of PS3-4 (9 months, 4 months, p = 0.03). CSF shunt surgery yielded patients beneficial rapid improvement in 94% of patients of their performance status.Conclusion: Combination of molecular targeting therapy and CFS shunt is a safe and effective strategy in patients with LAC-LM-H. Further clinical investigations are needed to clarify appropriate assessments and treatment indication for patients with LAC-LM-H.

Impact of EGFR tyrosine kinase inhibitors versus chemotherapy on the development of leptomeningeal metastasis in never smokers with advanced adenocarcinoma of the lung

This study investigated whether epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) increase the development of leptomeningeal metastasis (LM) compared with standard chemotherapy in EGFR mutation-enriched non-small cell lung cancer. The incidence of LM was longitudinally assessed in never smokers with advanced adenocarcinoma of the lung enrolled in a phase III randomized controlled study that compared gefitinib with gemcitabine plus cisplatin (GP) as first-line therapy (The First-SIGNAL study). Among 203 patients who were enrolled at the National Cancer Center Hospital (Goyang, Republic of Korea), LM occurred in 32 (15.8%) with a minimum follow-up time of 55.1months. The 1-, 2-, and 3-year actuarial incidence rates of LM were 5.3, 10.6, and 24.6%, respectively. During first-line treatment, LM occurred in 2 patients (2.0%) treated with gefitinib and in 3 patients (3.2%) treated with GP. There was no difference in the incidence of LM during first-line treatment between the two groups (P=0.934). The incidence of LM was significantly increased during second-line EGFR-TKI treatment compared with first-line EGFR-TKI treatment (P=0.041). During the disease course, the cumulative incidence of LM was not significantly different between the two treatment groups (P=0.514). The median time to LM was 21.4 and 24.0months in the gefitinib and GP groups, respectively (P=0.895). Similar trends were observed in the subset analysis with 23 EGFR-mutant patients. In conclusion, LM predominantly occurred in the late phase of disease in this population. EGFR-TKIs did not affect the incidence or timing of LM development.

Prospective follow-up of 96 patients with breast cancer with leptomeningeal metastasis recruited from 2007 to 2010.

2089 Background: Around 5% of patients with breast cancer (BC) develop leptomeningeal metastasis (LM). Incidence of LM may increase. The aim of this study was to report the outcome of patients diagnosed with BC LM. Methods: 96 consecutive female BC patients diagnosed with LM were prospectively followed up in our institution from 2007 to 2010. Characteristics and outcomes of patients were reported. Correlations between characteristics and overall survival (OS) were analyzed using usual statistical methods (Kaplan Meier, Log-rank, Cox). Results: Median time between BC and LM was 42,5 months. BC were invasive ductal carcinoma in 72%. Estrogen and progesterone receptors were detected in respectively 61,5 and 43% of the tumors. HER2 expression was observed in 26,5%. 24% were triple negative. At LM diagnosis, median age was 52 and median Performance Status (PS) was 2. CSF cytology and cerebrospinal MRI were positive in respectively 72% and 87%. Median time between LM diagnosis and 1st intrathecal (IT) was 3 days. 80 LM patients received IT liposomal cytarabine (ventricular device in 55%) associated with systemic treatment in 52 cases and whole brain radiotherapy in 12 cases. Clinical stabilization or improvement was observed in 46%, CSF response in 37%, MRI stabilization or improvement in 67,5%. 12 patients were staying alive. Median OS of the whole cohort and the 80 treated patients were respectively 2,8 and 3,5 months. Initial PS was the mainly variable correlated with OS (p<0,0001). Median OS of the whole cohort was 5 months in 0-2 PS patients (n=56), 24 days in 3-4 PS patients (n=40). Median OS of the treated patients was 5,6 months in 0-2 PS patients (n=50), 31 days in 3-4 PS patients (n=30). Other significant predictors of survival were: RP and triple negative status RP (p=0,01/p=0,004), time between LM diagnosis and 1st IT injection (p), systemic and IT treatment (p<0,0001/p=0,0002), radiotherapy (p=0,0076), clinical, cytological and MRI responses (p<0,0001/p=0,0366/p=0,0343). Conclusions: Our results confirm the importance of an early diagnosis and the interest of the association of IT and systemic treatment in treating BC LM.

Clinicopathological features of breast cancers predict the development of leptomeningeal metastases: a case-control study

The incidence of leptomeningeal metastases (LM) in patients with breast cancer (BC) is increasing as a result of increased screening and improved patient survival. However, the median survival time after diagnosis of LM is between 5 weeks (without any treatment) and 5 months (for aggressively treated patients). In an attempt to identify clinicopathological risk factors for LM, we carried out a case-control study of 100 women with BC. Fifty patients with BC and LM were enrolled and an additional 50 patients with BC and no CNS metastases including leptomeningeal spread were selected as controls. Patients who had developed LM were selected between December 2006 and August 2008. The control group was matched for: age at diagnosis, year of diagnosis, and initiation of chemotherapy at BC diagnosis. The ILC type (P = 0.03), ER-negative (P = 0.01) and PR-negative status (P = 0.03), and initial M+ status at BC diagnosis (P = 0.008) tended to be more frequent in LM patients. These characteristics should lead to early appropriate assessments being performed in this targeted population when a neurological complaint appears, in order to detect LM as soon as possible.

Comparison of Clinical Outcomes of Surgery Followed by Local Brain Radiotherapy and Surgery Followed by Whole Brain Radiotherapy in Patients With Single Brain Metastasis: Single-Center Retrospective Analysis

Data comparing the clinical outcomes of local brain radiotherapy (LBRT) and whole brain RT (WBRT) in patients with a single brain metastasis after tumor removal are limited. A retrospective analysis was performed to compare the patterns of treatment failure, cause of death, progression-free survival, median survival time, and Karnofsky performance status for long-term survivors among patients who underwent surgery followed by either LBRT or WBRT between 1990 and 2008 at the National Cancer Center Hospital. A total of 130 consecutive patients were identified. The median progression-free survival period among the patients who received postoperative LBRT (n = 64) and WBRT (n = 66) was 9.7 and 11.5 months, respectively (p = .75). The local recurrence rates (LBRT, 9.4% vs. WBRT, 12.1%) and intracranial new metastasis rate (LBRT, 42.2% vs. WBRT, 33.3%) were similar in each arm. The incidence of leptomeningeal metastasis was also equivalent (LBRT, 9.4% vs. WBRT, 10.6%). The median survival time for the LBRT and WBRT patients was 13.9 and 16.7 months, respectively (p = .88). A neurologic cause of death was noted in 35.6% of the patients in the LBRT group and 36.7% of the WBRT group (p = .99). The Karnofsky performance status at 2 years was comparable between the two groups. The clinical outcomes of LBRT and WBRT were similar. A prospective evaluation is warranted.

Méningites carcinomateuses des cancers du sein surexprimant HER2 : pour un traitement spécifique ?

Leptomeningeal metastases are very commonly associated with breast cancer. The prognosis is very poor in the short term with an overall median survival less than 6 months. Based on pragmatic and historical considerations intrathecal chemotherapy (IT) are considered to be the adequate treatment. However overall results are disappointing. Despite specific and symptomatic treatment, improvement in survival and quality of life remains very modest, highlighting the importance for ongoing research for developing new molecules or on improving the use a better use of those available today. The incidence of leptomeningeal metastases is particularly marked in cases of overexpression of HER2. The main hypothesis is there may be a better control of extra-cerebral localisations with trastuzumab therefore intra-cerebral recurrences may be encountered preferentially as they are not reached by this high molecular weight monoclonal antibody (148kD). Analyses performed in the cerebrospinal fluid following intravenous trastuzumab showed extremely low levels of the antibody and support the hypothesis that leptomeningeal metastasis of HER2-overexpressing breast carcinoma remain potentially sensitive to HER2-type receptor inhibition by a target agent under the condition of by-passing the meningeal blood brain barrier. Intra-ventricular or IT administered with trastuzumab would reach high loco-regional therapeutic concentrations in the cerebro-meningeal without risk for normal non-expressing HER2 leptomeningeal tissue. This strategy has been successfully tested on several animal models. A limited number of administrations in humans have been described in the literature, with weekly doses up to 100mg. No specific toxicity has been described and some data suggest a potential benefit in survival despite the real difficulties for adequate interpretations. Furthermore, a multicentric phase I-II clinical trial, of which the Curie institute is the sponsor and investigating the intra-thecal administration and the efficacy of the trastuzumab will begin very soon. More studies are needed to measure the exact impact of small molecule inhibitors of tyrosine kinase on the leptomeningeal localizations.

Early detection of leptomeningeal metastasis in patients with metastatic breast carcinoma: validation of CA 15-3 measurement in cerebrospinal fluid

Fifteen per cent of metastatic breast cancer will develop symptomatic leptomeningeal metastases. The introduction of trastuzumab (Herceptin) therapy has improved the response rates of survival of patients with metastatic breast cancer overexpressing HER2. Although previous studies are retrospective and of limited number, involving small study groups and different types of patient management, several authors have reported a 30% incidence of leptomeningeal metastases in patients with metastatic breast cancer overexpressing HER2 who were treated with trastuzumab, while 70 to 80% of cases of the disease were controlled systemically. In order to improve control of the disease at the level of the central nervous system (CNS), routine detection of leptomeningeal metastases in high-risk patients could be offered. CA 15-3 in cerebrospinal fluid (CSF) detection might be useful in helping to diagnose CNS metastases, particularly where cytology results are negative--which applies to 30% of cases--because tumor markers are more sensitive in detecting the tumor process. Our study validate CA 15-3 measurement in CSF and reference values were given.

Leptomeningeal metastases from solid malignancy: a review

Leptomeningeal metastases (LMM) consist of diffuse involvement of the leptomeninges by infiltrating cancer cells. In solid tumors, the most frequent primary sites are lung and breast cancers, two tumors where the incidence of LMM is apparently increasing. Careful neurological examination is required to demonstrate multifocal involvement of the central nervous system (CNS), cranial nerves, and spinal roots, which constitute the clinical hallmark of the disease. Cerebro-spinal fluid (CSF) analysis is almost always abnormal but only a positive cytology or demonstration of intrathecal synthesis of tumor markers is diagnostic. T1-weighted gadolinium-enhanced sequence of the entire neuraxis (brain and spine) plays an important role in supporting the diagnosis, demonstrating the involved sites and guiding treatment. Radionuclide CSF flow studies detect CSF compartmentalization and are useful for treatment planning. Standard therapy relies mainly on focal irradiation and intrathecal or systemic chemotherapy. Studies using other therapeutic approaches such as new biological or cytotoxic compounds are ongoing. The overall prognosis remains grim and quality of life should remain the priority when deciding which treatment option to apply. However, a sub-group of patients, tentatively defined here, may benefit from an aggressive treatment.

Angiostatin prolongs the survival of mice with leptomeningeal metastases.

As a result of the more effective treatment of primary tumours, the incidence of leptomeningeal metastases (LM) is increasing. Current treatment modalities have little effect on the survival of patients with LM. We investigated whether antiangiogenic treatment inhibits the progression of leptomeningeal tumours. To assess the role of angiogenesis in leptomeningeal tumours, we inoculated melanoma cells in the subarachnoid space in balb/c mice. At different stages, the mice were sacrificed and the microvessel density was determined. Human specimens of LM were compared with the mouse model. For the intervention studies, the mice were treated with the angiogenesis inhibitor angiostatin. Survival was the endpoint in these studies. Tumour seeding in the early disease stages was concentrated around the pre-existent arachnoid vasculature. In the more advanced stages, the tumour masses covered larger areas of the leptomeninges. Arachnoidal microvessel density in this advanced stage was increased compared with control mice. Systemic treatment of the mice with LM with angiostatin (100 mg kg-1 day-1) resulted in prolonged survival compared with mice treated with vehicle and with approximately one-fifth of the long-term survivors of the angiostatin-treated group. This study shows that neovascularization is important in the growth of LM in mice. Systemic targeting of the vascular compartment may be a useful approach in novel therapeutic strategies for patients with LM.

Role of endoscopic ultrasonography in the study of extrahepatic cholestasis

Leptomeningeal metastasis (LM) results from dissemination of cancer cells to both the leptomeninges (pia and arachnoid) and cerebrospinal fluid (CSF) compartment. Breast cancer, lung cancer, and melanoma are the most common solid tumors that cause LM. Recent approval of more active anticancer therapies has resulted in improvement in survival that is partly responsible for an increased incidence of LM. Neurologic deficits, once manifest, are mostly irreversible, and often have a significant impact on patient quality of life. LM-directed therapy is based on symptom palliation, circumscribed use of neurosurgery, limited field radiotherapy, intra-CSF and systemic therapies. Novel methods of detecting LM include detection of CSF circulating tumor cells and tumor cell-free DNA. A recent international guideline for a standardization of response assessment in LM may improve cross-trial comparisons as well as within-trial evaluation of treatment. An increasing number of retrospective studies suggest that molecular-targeted therapy, such as EGFR and ALK inhibitors in lung cancer, trastuzumab in HER2 + breast cancer, and BRAF inhibitors in melanoma, may be effective as part of the multidisciplinary management of LM. Prospective randomized trials with standardized response assessment are needed to further validate these preliminary findings.