Leptomeningeal Carcinomatosis In Patients Research Articles

Discrimination of leptomeningeal carcinomatosis and meningeal inflammation/infection with internal acoustic canal enhancement

PurposeThe purpose of this study is to investigate whether the presence and pattern of enhancement at the internal acoustic canal (IAC) could help in discriminating between leptomeningeal carcinomatosis (LCa) and meningeal inflammation/infection (MMI). MethodsMagnetic resonance (MR) images of patients with leptomeningeal enhancement were retrospectively evaluated. MR images of the LCa group (n = 33), MMI group (n = 19) and control group (n = 33) were evaluated for the presence, type (moderate/prominent), and localization (unilateral/bilateral) of the IAC enhancement. ResultsThe presence of IAC enhancement was significantly more common in patients with LCa (p < 0.001). In 73.7 % of patients with MMI, no contrast enhancement was observed in the IAC. In patients with contrast enhancement in the IAC, the risk of LCa in the etiology is 20 times greater than the risk of having MMI. Seventy-five percent of the IAC enhancement seen in LCa patients and 20 % of the IAC enhancements seen in MMI patients was bilateral. This difference was statistically significant (p = 0.029). ConclusionIntense contrast enhancement of the IAC can be a marker for LCa.

Clinical Outcomes of Subclinical Leptomeningeal Carcinomatosis in Patients Undergoing Stereotactic Body Radiation Therapy (SBRT) for Spinal Bone Metastases

Clinical Outcomes of Subclinical Leptomeningeal Carcinomatosis in Patients Undergoing Stereotactic Body Radiation Therapy (SBRT) for Spinal Bone Metastases

A nanowire-based liquid biopsy method using cerebrospinal fluid cell-free DNA for targeted management of leptomeningeal carcinomatosis.

This study aimed to evaluate whether genotyping cell free DNA (cfDNA) in the cerebrospinal fluid (CSF) may be helpful in managing leptomeningeal carcinomatosis (LMC) of EGFR-mutant non-small cell lung cancer (NSCLC). Patients with EGFR-mutant NSCLC who progressed as LMC after 3rd-generation tyrosine kinase inhibitors (EGFR-TKIs) were evaluated. A nanowire-based cfDNA assay was performed for genotyping cfDNA from the CSF and plasma. We focused on de novo EGFR C797S mutation and MET amplification, which are the most common mechanisms of resistance to 3rd-generation EGFR-TKIs. Among 11 patients, five (45.5%) had progression only at the leptomeninges. The tumor-associated CSF-cfDNA was identified in eight (72.7%) patients, and plasma-cfDNA in six (54.5%) patients. In the CSF-cfDNA, EGFR C797S mutation and MET amplification were detected in four (36.3%) and two (18.2%) patients, respectively. Of four patients with the C797S-positive LMC, only one had concurrent CSF-T790M mutation. Three patients who had the C797S-positive LMC without CSF-T790M mutation, received 1st-2nd generation EGFR-TKIs and showed clinical benefits for 20.8, 17.8, and 8.8weeks, respectively. Serial assessment with cfDNA in these patients demonstrated that the CSF levels of C797S mutation were decreased with radiological or neurological improvement but the plasma levels of T790M mutation were markedly increased before objective progression. Genotyping CSF-cfDNA by the nanowire-based assay is feasible and effective in guiding the treatment of LMC in patients with EGFR-mutant NSCLC.

Impact of clinicopathologic features on leptomeningeal metastasis from lung adenocarcinoma and treatment efficacy with epidermal growth factor receptor tyrosine kinase inhibitor.

BackgroundWe investigated the risk factors for leptomeningeal carcinomatosis (LMC) and compared clinical efficacies of various treatment modalities including intrathecal (IT) chemotherapy in patients with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations.MethodsUsing clinical research data from the Asan Medical Center, we retrospectively analyzed data of patients diagnosed with LMC, confirmed via cerebrospinal fluid (CSF) analysis from January 2008 to December 2017.ResultsWe identified 1189 patients with lung adenocarcinoma harboring EGFR mutations. Among these, 9.8% had a median duration of 13.5 (interquartile range [IQR] 6.8–23.6) months from the initial lung cancer diagnosis to LMC occurrence. Younger age (hazard ratio [HR] 1.043, P < 0.001), initial metastatic disease (HR 3.768, P < 0.001), and metastasis to the brain (HR 8.682, P < 0.001) or lung (HR 2.317, P = 0.004) were risk factors associated with LMC. Median survival duration from LMC diagnosis was 3.8 (IQR 1.5–8.6) months. Eastern Cooperative Oncology Group performance status score ≤ 2 (HR 0.505, P = 0.007) and insertion of Ommaya reservoir (HR 0.445, P = 0.005) were associated with longer survival. EGFR‐tyrosine kinase inhibitor (TKI) conferred survival benefits compared to cytotoxic chemotherapy or best supportive care (HR 2.222, P = 0.018; HR 5.638, P < 0.001, respectively). Although IT chemotherapy showed no survival benefit, it was associated with improved neurologic symptoms and signs and CSF negative conversion.ConclusionsYounger age, initial diagnosis of metastatic disease, and metastasis to the brain or different lobes were associated with LMC in patients with EGFR‐mutant lung adenocarcinoma. Therapeutic interventions including EGFR‐TKIs, cytotoxic chemotherapy, or Ommaya reservoir, and good performance status were related to favorable survival outcomes.Key pointsAge and disease status were associated with LMC in patients with EGFR‐mutant adenocarcinoma, and EGFR‐TKI, Ommaya reservoir, and good performance status were related to survival benefit.

EP1.01-13 A Phase 2 Trial Assessing Osimertinib Activity Against Leptomeningeal Carcinomatosis in EGFR-Mutant Lung Cancer

Leptomeningeal carcinomatosis (LMC) occurs in 10 % of EGFR-mutant lung adenocarcinoma (LA). Retrospective studies have suggeted a clinical benefit of osimertinib in treating LMC in patients with EGFR-mutant LA. We conducted a phase 2 prospective trial to demonstrate the clinical efficacy, activity, and LMC-specific mechanisms of resitance to osimertinib in EGFR-mutant LA patients. We performed gadalidium-enhanced brain MRIs at the time of enrollment, followed by scheduled brain imaging once every six weeks. Clinical neurological exams were performed every four weeks. Adverse Events (AEs) were assessed by NCI-CTCAE Ver. 4. Cerebral spinal fluid (CSF) and plasma was obtained on day 1 and 21 for all patients. The CSF osimertinib penetration rate was measured by liquid-chromatography mass spectrometry (LC-MSMS) and compared to plasma osimertinib levels. Targeted droplet digital PCR (ddPCR) was used to detect copy number changes of Met and the EGFR C797S mutation in patients CSF-DNA and plasma cell free (cf) DNA. We enrolled six pre EGFR-TKI treated EGFR mutant LA with LMC. We observed a LMC-specific progression free survival of 3.7 months and overall survival of 6.2 months or longer with osimertinib. Four and three of six patients showed neurological and radiological responses, respectively. No patients had any AEs greater than grade 3 and all patients continued osimertinib beyond PD. The osimertinib CSF penetration rate was 1.2±0.5%. Met copy number was normal in plasma, but increased in the CSF of 2/6 patients prior to progression. Met copy number was confirmed in 1/6 patients at the time of progression. An aquired EGFR C797S mutation was observed in 1/6 patients prior to progression.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Osimertinib 80 mg is efficacious in the treatment of LMC in EGFR mutated LA. CSF-specific MET copy number gain and EGFR C797S mutations arise prior to progression in EGFR-mutant LA patients treated with osimeritinib.

Abstract OT1-06-01: ANG1005 in leptomeningeal disease (ANGLeD) trial: A randomized, open-label, phase 3 study of ANG1005 compared with Physician's Best Choice in HER2-negative breast cancer patients with newly diagnosed leptomeningeal carcinomatosis and previously treated brain metastases

Abstract Background: Annually, more than 4,000 patients are diagnosed with leptomeningeal carcinomatosis (LC) from breast cancer in the U.S. Since most therapies cannot cross the Blood-CSF-Barrier (BCB) and the Blood-Brain-Barrier (BBB), treatment options for LC are limited to local radiation and few chemotherapy agents, none of which have provided durable clinical benefit, leading to short overall survival (OS) of 3-4 months. ANG1005 is a novel peptide-drug conjugate, consisting of 3 paclitaxel molecules covalently linked to a peptide that targets the LRP-1 receptor to cross both BCB and BBB, and enter the tumor cells, where the paclitaxel is cleaved off to exert its anti-tumor activity. ANG1005 has previously shown in a phase 2 study to prolong OS in LC patients from breast cancer with brain metastases (BM) to 8 months. Trial Design: This is an open-label, multi-center phase 3 randomized study to evaluate the efficacy of ANG1005 in HER2-negative breast cancer patients with newly diagnosed LC and documented history of previously treated BM when compared to Physician Best Choice (PBC). Hundred and fifty (150) patients will be randomized 1:1 to receive either ANG1005 experimental treatment or an Investigator assigned PBC control treatment. ANG1005 will be administered by intravenous (IV) infusion at a starting dose of 600 mg/m2 every 3 weeks. Allowed PBC therapies include capecitabine, eribulin, or high-dose IV methotrexate. CNS disease (LC and BM) will be evaluated at screening and every 6 weeks by MRI, CSF cytology and neurological assessments according to LANO and RANO-BM criteria. Extracranial disease will be evaluated by CT scans according to RECIST at screening and every 6-12 weeks. All patients will be followed for survival every 6-8 weeks from the date of the last dose until death, lost to follow-up or consent withdrawal. Eligibility Criteria: Eligible patients are adults (≥ 18 years old) with HER2-negative breast cancer, newly diagnosed LC and documented history of previously treated BM. Patients must be neurologically stable and have adequate blood counts, organ and bone marrow function with an ECOG status grade ≤2. Patients previously treated with ANG1005 or with known allergy to paclitaxel or its components are excluded. Specific aims: The primary endpoint is OS. Secondary endpoints include CNS (LC and BM) progression-free survival and clinical benefit rate, 6- and 12-month OS rates, LC response rate and duration of response, OS for triple negative patients and safety. Statistical Methods: This study is sized for testing the hypothesis of improved OS for ANG1005 versus PBC in all patients (HR=0.58, two-sided test, overall type 1 error of 5%). Interim analysis for OS (using O'Brien Fleming boundaries for efficacy and a fixed HR=1 for futility) will be performed when a total of 55 death events are reached across both arms. Study Accrual: Target accrual is 150 patients. The study is currently planned to start in the fall of 2018. Citation Format: Kumthekar P, Lawrence B, Iordanova V, Ibrahim N, Mazanet R. ANG1005 in leptomeningeal disease (ANGLeD) trial: A randomized, open-label, phase 3 study of ANG1005 compared with Physician's Best Choice in HER2-negative breast cancer patients with newly diagnosed leptomeningeal carcinomatosis and previously treated brain metastases [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-06-01.

Leptomeningeal carcinomatosis in patients with breast cancer.

Leptomeningeal carcinomatosis (LC) is defined as infiltration of the leptomeninges by metastatic carcinoma, a relatively uncommon but devastating complication of many malignancies. Although only 5% of patients with breast cancer develop leptomeningeal involvement, it remains the most common etiology of LC. It can occur as a late-stage complication of systemic progression or present as the first sign of metastatic disease, with or without parenchymal brain metastases. Lobular carcinomas have a higher propensity to metastasize into the meninges when compared to ductal carcinoma, especially the triple-negative subtype, which usually is associated with a shorter interval between metastatic breast cancer diagnosis and the development of LC. Prognosis remains poor, with median survival of 4 months for patients receiving state-of-the-art treatment. The main factors associated with survival are performance status at diagnosis, CSF protein level and triple-negative subtype. Headache is commonly the first clinical presentation of LC, and the diagnostic workup usually requires CSF-cytological analysis and or/MRI. The current management of LC consists of a combination of intra-CSF chemotherapy, systemic therapy, radiotherapy and/or best-supportive care. The standard intra-CSF chemotherapy regimen is methotrexate. Radiotherapy is used for relieving obstruction points on CSF-outflow channels due to ependymal nodules, tumor deposits or bulky disease. Objective responses have been reported with intrathecal administration of trastuzumab for HER2-positive disease, yet this strategy is still under investigation. Further prospective trials are needed to better address the impact of these treatment modalities on overall survival and quality of life.

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 rateswere 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 metastasesbefore SRS was associated with a 6.5 times higher odds (95% CI 1.45-29.35, p = 0.01) of developing LMC post-radiosurgerycompared tothose 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.

P2.01-033 Leptomeningeal Metastasis from Non-Small Cell Lung Cancer: A Single Center Experience in Chinese Patients

Leptomeningeal carcinomatosis (LM) is a rare type of metastatic tumors of the central nervous system. In recent years, with the improvement of neoplasms therapies and longer survival of patients by better systemic control, incidence of LM has increased every year. The incidence of LM in patients with non-small cell lung cancer (NSCLC) ranges from 1%-5%.However, no standard therapy has been established yet. This study is to investigate the clinical characteristics and prognostic factors of LM from NSCLC and to develop better treatment strategies. We collected and reviewed retrospectively the clinical characteristics, treatment methods as well as the outcomes of 45 consecutive patients with LM from NSCLC diagnosed and treated in our hospital from 2002 to 2017.Survival rates were analyzed using the Kaplan-Meier method. The multi-variate Cox proportional hazards model was used to determine the independent prognostic factors associated with improved survival. Among 45 patients who were enrolled, 7 (15.6%) had EGFR 19 deletion, 2 (4.4%) had EGFR 20 mutation, 22 (48.9%) had EGFR 21 mutation, 1 (2.2%) had EGFR 18 and also EGFR 20 mutation (T790M negative), 2 (4.4%) were ALK-positive, 5(11.1%) were EGFR wild-type, 6 (13.3%) patients didn't perform EGFR test. The median overall survival from the diagnosis of LM for all the patients was 15（range, 1–34）months. Gender, gene mutation and Tyrosine kinase Inhibitors (TKIs) treatment were correlated with survival time for the patients (P<0.05 for all). Other prognostic variables such as age, initial ECOG, time to leptomeningeal dissemination, CSF cytology, CSF pressure, CSF biochemical, brain radiotherapy, chemotherapy and intrathecal chemotherapy were not statistically correlated to overall survival. In the multivariate analysis, Cox proportional hazard regression showed that TKIs treatment was the independent prognostic factor (P<0.05). TKIs treatment was the independent prognostic factor for leptomeningeal metastases from non-small cell lung cancer. We suggest that in LM patients from NSCLC giving TKIs treatment may prolong survival.

Intrathecal trastuzumab for leptomeningeal carcinomatosis in patients with human epidermal growth factor receptor 2 positive breast cancer

There has been recent increase in incidence of leptomeningeal carcinomatosis, possibly due to widespread use of adjuvant trastuzumab and its known poor CNS penetration. Currently there are limited therapeutic options for these patients and outcome is poor. We report two cases of women with HER2 positive breast cancer who developed leptomeningeal carcinomatosis for which they were treated with intrathecal trastuzumab in combination with systemic therapy. Both patients had rapid symptomatic benefit and radiological response and remained progression free for at least seven months. Intrathecal trastuzumab can be considered a reasonable therapeutic option for these difficult to treat patients.

Intravenous thiotepa for treatment of breast cancer-related leptomeningeal carcinomatosis: case series.

Leptomeningeal carcinomatosis (LMC) secondary to metastatic breast cancer (MBC) has increased in incidence with improved systemic disease control. Current treatment options include radiation therapy (to symptomatic sites) and systemic treatment [intrathecal (IT) or intravenous (IV) chemotherapy]. Methotrexate (MTX), thiotepa and cytarabine are the most commonly used IT agents, while high-dose MTX is the most common IV regimen. While IT treatments are generally well tolerated, complications like chemical meningitis, leukoencephalopathy, etc. occur. LMC may cause a breakdown in the blood-brain barrier and thus allow systemic agents to penetrate; however, efficacy is reported only for agents administered at high doses (MTX). We report our institution's experience in using IV thiotepa as treatment for LMC secondary to MBC. We conducted a retrospective chart review of 13 patients with MBC who developed LMC and treated with IV thiotepa at our institution. It was administered at 40 mg/m(2) every 21 days; median number of thiotepa cycles administered was 5 with the major dose-limiting toxicity being myelosuppression. Four had partial response, 3 had stable disease and 6 had progressive disease. The 6-month survival rate was 69 % and 1-year survival rate was 31 %. Despite retrospective nature of our case series, we found the use of IV thiotepa as sole treatment for LMC in patients with MBC to be well tolerated, easily administered in the ambulatory setting, and with efficacy comparable to the other chemotherapeutic agents commonly used in the treatment of LMC. This regimen warrants further investigation in prospective studies.

Frequent development of leptomeningeal carcinomatosis in patients with peritoneal dissemination of gastric cancer

We detected 7 cases of leptomeningeal carcinomatosis in 126 patients with peritoneal dissemination of gastric cancer who received combined systemic and intraperitoneal chemotherapy. Leptomeningeal carcinomatosis was diagnosed 79-1540days after the diagnosis of the primary gastric cancer. Patients presenting with various neurological symptoms were diagnosed by cerebrospinal fluid (CSF) cytology and radiological imaging. Irradiation to the whole brain and spine was performed in 4 patients, and provided palliation and increased survival for 1 patient. Intrathecal chemotherapy and drainage of CSF was performed in 1 patient each, but produced no significant clinical benefit in either of them. Survival after the diagnosis of leptomeningeal carcinomatosis was between 3 and 155days. As patients with peritoneal dissemination of gastric cancer are living longer because of improved chemotherapy, clinicians must recognize the possibility of leptomeningeal carcinomatosis when patients complain of neurological symptoms.

Approaching an individual methotrexate regimen in leptomeningeal carcinomatosis

Background Chemotherapeutic effects in leptomeningeal carcinomatosis (LC) vary widely between patients, presumably in part because drug elimination from cerebrospinal fluid (CSF) differs between individuals. An individual dosing, adapted to elimination, may improve treatment efficacy. Objective To discuss the feasibility of easily accessible elimination parameters for an individual dosing of chemotherapy in LC. Materials and methods The elimination of intrathecally applied methotrexate (Mtx) was tested in 14 LC patients and compared to the literature data. Plasma drug levels and CSF albumin levels are suggested as elimination parameters. Results and discussion Mtx disappeared from CSF and appeared in plasma with an expected wide variation (interindividual range of coefficients of variation (CV) of CSF Mtx levels 158–189%, intraindividual range of CV of plasma Mtx levels 35–64%). Our data together with reported data suggest that plasma Mtx levels mirror closely the Mtx elimination from CSF. The levels of CSF albumin and of plasma Mtx at defined sample times correlated negatively ( r = − 0.7), which reflects their largely common elimination from CSF. Conclusion Both parameters seem appropriate to describe the Mtx elimination from CSF. They should allow to individually adapt Mtx dosing towards an improvement of Mtx availability in CSF and of treatment efficacy.

Creatine kinase-BB in the cerebrospinal fluid as a marker of CNS metastases and leptomeningeal carcinomatosis in patients with breast cancer

To determine whether creatine kinase-BB isoenzyme would be useful in detecting central nervous system metastases secondary to breast cancer, we measured the cerebrospinal fluid (CSF) activity of creatine kinase (CK) and its BB isoenzyme (CK-BB) in 65 consecutive patients suspected of having CNS involvement.All patients underwent neurological evaluation, computer tomography (CT) scan and/or radionuclide scintigraphy and lumbar puncture with CSF examination.Thirty patients had CNS metastases, of whom 18 had parenchymal brain metastases (MET). Twelve had leptomeningeal carcinomatosis (MC), of whom four also had parenchymal brain metastases. Thirty-four patients were concluded not to have CNS involvement, whereas one was considered equivocal.CK-BB activity was significantly higher in patients with CNS metastases than in those without (P <0.05). This difference was primarily related to the fact that patients with MC had a significantly higher CK-BB activity than patients without CNS metastases or patients with parenchymal brain metastases only (P <0.01 and P <0.05, respectively). Taking 0.20 U/l as a tentative cut-off value (the upper limit range of patients without CNS metastases being 0.19 U/l), 10 out of 12 patients with MC had activities above this level. The sensitivity and specificity for having MC were 83% and 87%, and the positive and negative predictive values 60% and 96%, respectively. The sensitivity and negative predictive value for having any CNS metastases were 57% and 72%. Specificity and positive predictive value: 100%. The CSF activity of CK-BB appears to be a contribution in the diagnosis of MC secondary to breast cancer and seems superior to protein and LDH.