Treatment Of Leptomeningeal Disease Research Articles

Radiotherapy and Systemic Treatment for Leptomeningeal Disease.

Leptomeningeal disease (LMD) is a devastating sequelae of metastatic spread that affects approximately 5% of cancer patients. The incidence of LMD is increasing due to advancements in systemic therapy and enhanced detection methods. The purpose of this review is to provide a detailed overview of the evidence in the detection, prognostication, and treatment of LMD. A comprehensive literature search of PUBMED was conducted to identify articles reporting on LMD including existing data and ongoing clinical trials. We found a wide array of treatment options available for LMD including chemotherapy, targeted agents, and immunotherapy as well as several choices for radiotherapy including whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and craniospinal irradiation (CSI). Despite treatment, the prognosis for patients with LMD is dismal, typically 2-4 months on average. Novel therapies and combination approaches are actively under investigation with the aim of improving outcomes and quality of life for patients with LMD. Recent prospective data on the use of proton CSI for patients with LMD have demonstrated its potential survival benefit with follow-up investigations underway. There is a need for validated metrics to predict prognosis and improve patient selection for patients with LMD in order to optimize treatment approaches.

Early Outcomes from Proton Craniospinal Irradiation (pCSI) for Leptomeningeal Disease from Solid Tumors

Prospective data suggest that proton craniospinal irradiation (pCSI) improves overall survival (OS) in patients with leptomeningeal disease (LMD) from solid tumors, compared to the historical standard of involved field radiation. To evaluate outcomes of this novel approach in a real-world setting, our institutional experience with treating adults with pCSI for LMD from solid malignancies was evaluated. On an IRB-approved protocol, medical records of adults with LMD from solid tumors treated with pCSI were retrospectively reviewed for patient, disease and treatment characteristics and outcomes. CNS-PFS and OS were calculated from the last day of pCSI, and survival was modeled using Kaplan-Meier analysis. From December 2021 to November 2022, 17 patients with median age 51y (range 22-71y) were treated with pCSI for LMD from solid tumors. Thirteen patients (76%) were female. Ten had ECOG PS of 0-1, and seven had PS 2-3. Nine patients (53%) had breast cancer, 3 (18%) had non-small cell lung cancer (NSCLC), 2 (12%) had melanoma, 1 (6%) had colorectal adenocarcinoma, 1 (6%) had endocervical adenocarcinoma, and 1 (6%) had two synchronous primaries (adenocarcinoma of the gastro-esophageal junction and neuroendocrine carcinoma of the lung). All patients had prior radiation; ten had prior radiation to the brain, one had prior radiation to the spine, and six had other sites previously radiated. Fourteen patients (82%) were treated to 30 Gy in 10 fractions and 3 (18%) were treated to 25 Gy in 10 fractions due to overlap with prior radiation fields. Median follow-up was 4 months (range, 1-13 months). Among 15 evaluable patients, median CNS-PFS and median OS were 3.6 months and 4.7 months, respectively. For patients with breast cancer or NSCLC, 62% were alive at 6 months; median OS has not been reached. Treatment was well tolerated with no grade 3-4 non-hematologic adverse events. pCSI is a novel method for treatment of LMD from solid tumors that has been rapidly adopted. Based on our preliminary review, it is safe and well-tolerated; patient selection is critical. As these patients are often heavily pretreated, prior radiation fields must be considered in pCSI planning.

SURG-05. SUPERVISED MACHINE LEARNING IDENTIFIES RISK FACTORS ASSOCIATED WITH LEPTOMENINGEAL DISEASE AFTER SURGICAL RESECTION OF BRAIN METASTASES

Abstract INTRODUCTION Predictors of postoperative leptomeningeal disease (LMD) after resection of brain metastases (BMs) are not well defined. OBJECTIVE This study examined rates and predictors of LMD, including subtypes, in patients who underwent resection of a BM followed by postoperative radiation.Method: A retrospective, single-center study was conducted examining overall LMD, classical LMD (cLMD), and nodular LMD (nLMD) risk. Logistic regression and a Cox proportional hazards analyses were performed to identify risk factors associated with LMD. Random forest models were constructed to predict LMD and differentiate cLMD versus nLMD. Accuracy and the area under the receiver operating characteristic curve (AUROC) were calculated to evaluate the models.Result: Of the 217 patients in the cohort, 47 (21.7%) developed postoperative LMD with 19(8.8%) cLMD cases and 28(12.9%) nLMD cases . Six-, 12-, and 24-month LMD-free survival rates were 92.3%, 85.6%, and 71.4%, respectively. Patients with cLMD had worse survival outcomes from LMD diagnosis compared to nLMD (2.4 vs 6.9 mo, Log-rank p=0.02), and treatment of LMD was associated with improved survival for both cLMD and nLMD subtypes. Multivariate Cox hazard analysis identified cerebellar/insular/occipital location (HR 3.25, 95% CI 1.73-6.11, p=0.0003), absence of extracranial disease (HR 2.49, 95% CI 1.27-4.88, p=0.008), and ventricle contact (HR 2.82, 95% CI 1.5-5.3, p=0.001) to be associated with postoperative LMD. A predictive model using random forest analysis with an AUROC of 0.87 in a test cohort identified tumor location, systemic disease status, and tumor volume as the most important factors associated with LMD. Both regression analysis and random forest analysis identified postoperative systemic therapy exposure as the main factor differentiating cLMD from nLMD development. CONCLUSION Tumor location, absence of extracranial disease at the time of surgery, contact with a ventricle, and increased tumor volume are associated with LMD. Classical LMD is associated with worse prognosis compared to nLMD.

DDEL-02. LUMBAR OMMAYA RESERVOIR- A COST EFFECTIVE ALTERNATIVE TO INTRAVENTRICULAR OMMAYA RESERVOIR FOR TREATMENT OF LEPTOMENINGEAL DISEASE

Abstract Introduction Lumbar puncture (LP) is a well-established approach for intrathecal (IT) delivery of chemotherapeutics for leptomeningeal disease (LMD). Intraventricular Ommaya reservoir (OR) has supplanted LPs as an easier and safer route for IT administration. Radiotherapy for treatment of LMD must be delayed in order for surgical wound healing following OR placement. Furthermore, prior cranial radiation can thin the scalp, predisposing to wound breakdown. Placement of lumbar Ommaya reservoir (LOR) provides an alternative to IT delivery, but this has not reached a wide-spread acceptance. Objective Provide cost-analysis and report patient outcomes after placement of LOR. METHODS Following IRB approval, all patients undergoing LOR placement between 2018 and 2020 were retrospectively reviewed. Patients age, primary tumor, survival lengths and complications were reviewed. Average procedure-related treatment cost was obtained from an uncomplicated representative case excluding the surgeon’s fee. RESULTS Fourteen patients (mean age 46.35 years) were identified. The mean follow-up was 440.7 (25-1003) days post-surgery. Acute lymphoblastic leukemia (n = 4), acute myeloblastic leukemia (n = 3), breast carcinoma (n = 3), ependymoma (n = 3), lymphoma (n = 2) and lung adenocarcinoma (n = 1) were identified as underlying malignancy. LMD was diagnosed on average after 581.1 days after the diagnosis of the underlying malignancy. 8 patients succumbed to their malignancy on average after 463.9 and 314.6 days after the diagnosis of LMD and LOR surgery, respectively. There were 2 complications – pain at the site of the LOR and a fractured catheter caused by inadvertent puncture of the catheter. No infections or wound healing complications were noted. Typical cost for placement of LOR and OR was – 17,350 USD and 29,052 USD, respectively. Placement of the LOR proved to be more cost-effective in this cohort by approximately 40% cost reduction. CONCLUSION Placement of LOR is a cost effective alternative to cranial OR with low complication profile, and well tolerated by patients.

Advances in the Diagnosis and Treatment of Leptomeningeal Disease.

Leptomeningeal disease (LMD) is a rare, late complication of systemic cancer and is associated with significant neurological morbidity and high mortality. Here we provide an overview of this condition, summarizing key recent research findings and clinical practice trends in its diagnosis and treatment. We also review current clinical trials for LMD. Improved molecular diagnostic tools are in development to enable more sensitive detection of LMD, including circulating tumor cells and circulating tumor DNA. The use of targeted and CNS-penetrant therapeutics has shown survival improvements with tyrosine kinase inhibitors, antibody-drug conjugates, and select chemotherapy. However, these studies have primarily been phase I/II and retrospective analyses. There remains a dearth of clinical trials that include LMD patients. The combination of patient-specific molecular information and novel therapeutic approaches holds significant promise for improving outcomes in patients with LMD.

Challenges and Advances in Diagnosis and Treatment of Leptomeningeal Disease (LMD).

Leptomeningeal disease (LMD) is a devastating category of CNS metastasis with a very poor prognosis and limited treatment options. With maximal aggressive therapy, survival times remain short and, without treatment, prognosis is measured in weeks. Both LMD diagnosis and treatment are challenging topics within neuro-oncology. In this review, we discuss the advances in LMD diagnosis with a focus on the role of circulating tumor DNA (ctDNA) and discuss the role of targeted and immunotherapy in LMD treatment.

Leptomeningeal disease in glioblastoma: endgame or opportunity?

Glioblastoma is an aggressive cancer with a notoriously poor prognosis. Recent advances in treatment have increased overall survival, though this may be accompanied by an increased incidence of leptomeningeal disease (LMD). LMD carries a particularly severe prognosis and remains a late stage manifestation of glioblastoma without satisfactory treatment. The objective of this review is to survey the literature on treatment of LMD in glioblastoma and to more fully characterize the current therapeutic strategies. The authors performed a systematic review following PRISMA criteria on PubMed and OVID databases. Articles that included adult patients with LMD from glioblastoma were retrieved and reviewed. LMD in glioblastoma patients is increasing in incidence, with reports of up to 21%. The overall survival without treatment is alarmingly brief, with patients surviving between 1.6-3.8months. All studies showed that treatment does improve overall survival significantly, increasing to 11.7months in one study. However, no one adjuvant or surgical therapy has been shown to improve survival in LMD significantly over another. Direct treatment methods include chemotherapy (standard, anti-angiogenic, intrathecal, immunotherapy), and radiation. Hydrocephalus is a complication in LMD that can be treated with ventriculoperitoneal shunt placement, however treating hydrocephalus and delivering intrathecal chemotherapy is a challenge. Though evidence remains lacking and there is no consensus, treatments show a trend towards improving survival and should be considered on a case-by-case basis. Further studies are necessary in the pursuit of a standard of care.

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

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). 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. 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). 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.

Leptomeningeal metastases in glioma: The Memorial Sloan Kettering Cancer Center experience.

To perform a retrospective analysis examining the incidence and prognosis of glioma patients with leptomeningeal disease (LMD) at Memorial Sloan Kettering Cancer Center over a 15-year period and correlate these findings with clinicopathologic characteristics. We conducted a retrospective review of glioma patients with LMD at Memorial Sloan Kettering Cancer Center diagnosed from 2001 to 2016. Patients were identified through a keyword search of their electronic medical record and by ICD-9 codes. One hundred three patients were identified with disseminated LMD and 85 patients with subependymal spread of disease, 4.7% of all patients with glioma. These cohorts were analyzed separately for time to development of disseminated LMD/subependymal LMD, median overall survival, and survival from LMD diagnosis. Patients were pooled for subsequent analyses (n = 188) because of comparable clinical behavior. LMD was present at glioma diagnosis in 10% of patients. In the remaining 90% of patients diagnosed at recurrence, time to LMD diagnosis, survival after LMD diagnosis, and overall survival varied by original histology. Patients with oligodendroglioma had a median survival of 10.8 (range 1.8-67.7) months, astrocytoma 6.5 (0.1-28.5) months, and glioblastoma 3.8 (0.1-32.6) months after LMD diagnosis. In addition, we found that treatment of LMD was associated with superior performance status and increased survival. Patients with LMD diagnosed at relapse may not have decreased overall survival as compared to historical controls with parenchymal relapse and may benefit from treatment.

Successful Treatment of Leptomeningeal Disease in Colorectal Cancer With a Regimen of Bevacizumab, Temozolomide, and Irinotecan

Successful Treatment of Leptomeningeal Disease in Colorectal Cancer With a Regimen of Bevacizumab, Temozolomide, and Irinotecan

Intraventricular application of rituximab as a treatment option in patients with CNS lymphoma and leptomeningeal disease

1521 Background: Most patients (pts) with primary central nervous system lymphoma (PCNSL) relapse after initial response to treatment, often presenting with leptomeningeal disease. Since the majority of PCNSL are B-cell neoplasms expressing the CD20 surface antigen treatment with the chimeric monoclonal antibody (Mab) rituximab might be reasonable. The primary objective was to evaluate feasibility and safety of direct administration of the anti-CD20 antibody into the cerebro spinal fluid (CSF). Methods: Pts with intracranial lesions and/or leptomeningeal involvement of B-cell neoplasms expressing the CD20 surface antigen were included. In order to define the tolerated single dose, injections of 10–40 mg rituximab in a volume of 1–4 ml were administered over two minutes via an ommaya reservoir (n=4) or intrathecally (n=2). Drug clearance from the CSF was determined by measuring rituximab levels in the CSF and blood by ELISA. Results: Treatment with rituximab at single dosis of up to 35mg thrice weekly was safe and well tolerated in 5/6 pts. Acute neurotoxicity in one pt (PN6) was probably related to a high tumor cell burden in the CSF and a rapid tumor cell lysis after intrathecal rituximab. Measurement of rituximab concentrations in the CSF showed severalfold higher values after intraventricular administration compared to those after intravenous rituximab application. Clearing of tumor cells in the CSF and a complete remission of leptomeningeal lymphoma manifestation was achieved in four pts. However, there was no effect of rituximab on parenchymal lymphoma. Conclusions: Taken together, these data suggest that direct administration of rituximab into the CSF may have a role in the treatment of leptomeningeal disease in pts with CNS lymphoma. However, the therapeutic value of systemic treatment with the antibody remains questionable. To better define the value of rituximab treatment in CNS lymphoma with lymphomatous meningitis, future studies should investigate dose intensification as well as combination with other chemotherapeutic drugs or radiotherapy. No significant financial relationships to disclose.