Leptomeningeal disease (LMD) refers to the infiltration of cancer cells into the leptomeningeal compartment. Leptomeninges are the two membranous layers, called the arachnoid membrane and pia mater. The diffuse nature of LMD poses a challenge to its effective diagnosis and successful management. Furthermore, the predominant phenotype; solid masses or freely floating cells, has altering implications on the effectiveness of drug delivery systems. The standard of care is the intrathecal delivery of chemotherapy drugs but it is associated with increased instances of treatment-related complications, low patient compliance, and suboptimal drug distribution. An alternative involves administering the drugs systemically, after which they must traverse fluid barriers to arrive at their destination within the leptomeningeal space. However, this route is known to cause off-target effects as well as produce subtherapeutic drug concentrations at the target site within the central nervous system. The development of new drug delivery systems such as liposomal cytarabine has improved drug delivery in leptomeningeal metastatic disease, but much still needs to be done to effectively target this challenging condition. In this review, we discuss about the anatomy of leptomeninges relevant for drug penetration, the conventional and advanced drug delivery methods for LMD. We also discuss the future directions being set by different clinical trials.

Treating metastatic malignancies to the central nervous system (CNS) is challenging because many drugs cannot cross the blood-brain-barrier (BBB). Direct intrathecal (IT) drug administration into the cerebrospinal fluid (CSF) is a strategy to overcome this problem. Thiotepa has effective CNS penetration but its popularity has waned over the last two decades due to concerns about its efficacy and potential systemic toxicity. This review evaluates the available evidence for the use of IT thiotepa in hematologic malignancies and non-CNS solid tumors with leptomeningeal disease metastases (LMD). Our search shows that IT thiotepa is a reasonable alternative in hematologic malignancies and LMD due to solid organ malignancies. This suggests a potential role of IT thiotepa in second-or third-line treatment or a substitute role in cases of drug-shortages and adverse effects with other agents. Future research should focus on rigorous comparative trials to establish its definitive role in the evolving landscape of CNS-directed chemotherapy.

Leptomeningeal metastases are lesions of brain and/or spinal cord sheaths by tumor cells. They occur in 5% of patients with solid tumors, although autopsies reveal these lesions much more often (10-20% of cases). Leptomengeal metastases are an unfavorable prognostic factor. Despite the modern NCCN treatment standards, including intrathecal therapy (ITT), such patients receive only irradiation of the entire brain and/or spinal cord in most cases.
OBJECTIVE: To evaluate the effectiveness of ITT in patients with leptomeningeal metastases in breast cancer.
METHODS: Twenty-five patients with breast cancer and leptomeningeal metastases underwent intrathecal administration of methotrexate between 2016 and 2022. Intrathecal chemotherapy was administered through lumbar puncture. We performed an intensive course (intrathecal methotrexate 15 mg 2 times a week for 1 month (8 injections), then intrathecal methotrexate 15 mg 1 time a week (4 injections), and then 15 mg 1 time a month until progression or unacceptable toxicity).
RESULTS: The median duration of ITT was 2.5 months. Complete neurological responses were observed in 3 out of 25 (12%) patients, partial neurological response - in 15 out of 25 (60%) patients, progression of neurological symptoms - in 7 (28%) patients. The number of complete cytological responses was observed in 6 out of 25 (24%) patients. The median overall survival after ITT was 6.7 months.
CONCLUSIONS: Effectiveness of ITT is confirmed by higher quality of life (72% of patients), complete cytological responses (24%) and improvement in neuroimaging data. This is an important criterion for severe patients with limited treatment options. First-stage ITT before whole-brain irradiation is preferable, as this approach increases overall survival by 3 months. Undoubtedly, ITT is a treatment option that can be used in routine clinical practice for lesions of brain and spinal cord sheaths.
Лептоменингеальные метастазы — поражение опухолевыми клетками оболочек головного и/или спинного мозга. Развиваются у 5% больных с солидными опухолями, хотя на аутопсиях поражение оболочек выявляется значительно чаще — в 10—20% случаев. Лептоменингеальные метастазы считаются неблагоприятным фактором прогноза. Несмотря на имеющиеся стандарты лечения, по данным Национальной комплексной онкологической сети (National Comprehensive Cancer Network, NCCN), включающие интратекальную терапию (ИТТ), таким пациенткам в большинстве случаев проводится только облучение всего головного и/или спинного мозга.
UNASSIGNED: Оценка эффективности ИТТ у больных с лептоменингеальными метастазами при раке молочных желез (РМЖ).
UNASSIGNED: В отделении нейроонкологии ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России в период с 2016 по 2022 г. интратекальное введение метотрексата получили 25 больных РМЖ с лептоменингеальными метастазами. ИТТ-химиотерапия проводилась посредством люмбальной пункции. Интенсивный курс в дозе 15 мг метотрексата интратекально 2 раза в неделю в течение 1 мес (8 введений), далее по 15 мг метотрексата интратекально 1 раз в неделю (4 введения), далее по 15 мг 1 раз в месяц до прогрессирования или неприемлемой токсичности.
UNASSIGNED: Медиана длительности проводимой ИТТ составила 2,5 мес. Количество полных неврологических ответов отмечено у 3 (12%) из 25 пациенток. Частичный неврологический ответ — у 15 (60%) из 25 больных, у 7 (28%) пациенток отмечалось прогрессирование неврологической симптоматики. Количество полных цитологических ответов наблюдалось у 6 (24%) из 25 больных. Медиана общей выживаемости больных, получивших ИТТ, составила 6,7 мес.
UNASSIGNED: Эффективность лечения ИТТ подтверждена улучшением качества жизни больных (72%), полными цитологическими ответами (24%) и улучшением картины при нейровизуализации, что является немаловажным критерием для тяжелой категории больных с ограниченными лечебными опциями. Предпочтительнее проводить ИТТ на первом этапе лечения, до облучения всего головного мозга, поскольку это увеличивает медиану общей выживаемости на 3 мес. Несомненно, проведение ИТТ — это лечебная опция, которая может использоваться в рутинной клинической практике при поражении оболочек головного и спинного мозга.

Therapeutic management of patients with leptomeningeal carcinomatosis (LC) may require treatment of concomitant hydrocephalus (HC) in addition to intrathecal chemotherapy (ITC). Ventriculoperitoneal shunts (VPS) equipped with a valve for manual deactivation of shunt function and a concomitant reservoir for application of ITC pose an elegant solution to both problems. The present study evaluates indication, feasibility, and safety of such a modified shunt/reservoir design (mS/R). All patients with LC aged ≥ 18 years who had undergone mS/R implantation between 2013 and 2020 at the authors\' institution were further analyzed. ITC was indicated following the recommendation of the neuro-oncological tumor board and performed according to a standardized protocol. Sixteen patients with LC underwent mS/R implantation for subsequent ITC and concomitant treatment of HC. Regarding HC-related clinical symptoms, 69% of patients preoperatively exhibited lethargy, 38% cognitive impairment, and 38% (additional) visual disturbances. Postoperatively, 86% of patients achieved subjective improvement of HC-related symptoms. Overall, postoperative complications occurred in three patients (19%). No patient encountered cancer treatment-related complications. The present study describes a combination procedure consisting of a standard VPS-system and a standard reservoir for patients suffering from LC and HC. No cancer treatment-related complications occurred, indicating straightforward handling and thus safety.

Corticosteroid therapy is the mainstay of immune effector cell-associated neurotoxicity syndrome (ICANS) management, although its use has been associated with worse overall survival (OS) and progression-free survival (PFS) after chimeric antigen receptor T-cell (CAR-T cell) therapy. Many options are being investigated for prophylaxis and management. Accumulating evidence supports the use of intrathecal (IT) chemotherapy for the management of high-grade ICANS. Here, we describe a case of a patient with stage IV Primary mediastinal B-cell lymphoma (PMBCL) successfully treated with IT methotrexate, cytarabine, and dexamethasone as first-line therapy for CD19 CAR-T cell-associated grade IV ICANS. The stable and rapid resolution of ICANS to grade 0 allowed us to discontinue systemic corticosteroid use, avoiding CAR-T cells ablation and ensuring preservation of CAR-T cell function. The described patient achieved a complete radiologic and clinical response to CD19 CAR-T cell therapy and remains disease-free after 9 months. This case demonstrates a promising example of how IT chemotherapy could be used as first-line treatment for the management of high-grade ICANS.

Leptomeningeal metastasis (LM) is a complication of non-small cell lung cancer (NSCLC) characterized by poor prognosis and short survival. A variety of therapeutic approaches have been sought to improve the efficacy of LM. Here we present a clinical case and conduct a literature review to investigate the effectiveness and safety of double-dose osimertinib combined with a pemetrexed intrathecal injection. This is an older man who underwent thoracoscopic pneumonectomy and was diagnosed with stage IIA lung adenocarcinoma with EGFR21 L858R mutation. He experienced thoracic vertebral metastases 33 months postoperatively and received first-line treatment with gefitinib combined with radiotherapy for vertebral metastases. However, the patient developed a grade 3 rash with unacceptable toxicity and his CEA levels were significantly increased 22 months later, leading to a targeted treatment adjustment to 80 mg of osimertinib orally once daily. Four months later, the patient developed LM and osimertinib dosage was increased to 160 mg once daily; however, neurological symptoms did not improve, and cerebrospinal fluid (CSF) tumor cells remained detected. Accordingly, the patient received an intrathecal injection of pemetrexed (dose 30 mg) every 2-3 months, 2-3 times per course (4-6 days each time), and continued to receive a double dose of osimertinib. After three courses of intrathecal chemotherapy, CSF tumor cells were eliminated, and neurological symptoms significantly improved. During the treatment, he experienced a one-degree rash, leukopenia, thrombocytopenia, and fatigue. This patient has been alive and well with disease control for 28 months since the diagnosis of meningeal metastases. Combining double-dose osimertinib and an intrathecal injection of pemetrexed demonstrated therapeutic efficacy and manageable adverse effects in this patient with advanced NSCLC with EGFR-mutant and LM.

Cancer of unknown primary (CUP) and leptomeningeal metastasis are difficult conditions with limited treatment options. We report a case of CUP leptomeningeal metastasis that was refractory to empirical chemotherapy but achieved a favorable response to intrathecal trastuzumab after the identification of human epidermal growth factor receptor-2 (HER2) amplification. A 59-year-old woman was diagnosed with CUP with metastasis of a poorly differentiated carcinoma to the left axillary, anterior mediastinal, peritoneal, and bilateral supraclavicular lymph nodes. Leptomeningeal metastasis was confirmed shortly after she started empiric chemotherapy; empiric therapy with intrathecal methotrexate failed to relieve her symptoms. Meanwhile, the lymph node specimen tested positive for HER2 amplification. She underwent intrathecal trastuzumab, then her neurological symptoms resolved the following day. We suggest that intrathecal trastuzumab is an effective treatment for HER2-positive CUP leptomeningeal metastasis.

BACKGROUND: Leptomeningeal disease (LMD) secondary to high grade glioma (HGG), such as glioblastoma (GBM), are characterized by the spread of tumor cells to the leptomeninges which further complicates treatment approaches. Intrathecal (IT) chemotherapy has surfaced as a potential strategy to bypass the blood-brain barrier and address the challenges posed by disseminated disease. Here, we present a review of the safety and efficacy of IT chemotherapy in the treatment of LMD secondary to HGG.
METHODS: A systematic review following PRISMA guidelines was conducted searching PubMed and Embase from January 1995 to September 2022 using specified terms related to IT chemotherapy for LMD. Included articles involved patients diagnosed with LMD from HGG, treated with intrathecal chemotherapy, and provided survival data. Data, including demographics, tumor characteristics, treatment, and survival information, were collected and independently extracted.
RESULTS: A total of 68 patients across 10 clinical studies were diagnosed with LMD from HGG and included in the review. Among these patients, the average age at diagnosis was 44.2 years. GBM was the most common tumor type (n = 58, 85.3%). A majority of the patients presented with recurrent disease (n = 29, 60.4%). The review encompassed various IT chemotherapy regimens, including mafosfamide, thio-TEPA, 5-fluoro-2\'-deoxyuridine (FdUrd), methotrexate (MTX), and cytarabine; however, dosages and frequencies were inconsistently reported. The mean progression-free survival (PFS) and overall survival (OS) for this cohort were 7.5 months and 11.7 months, respectively. Common side effects of IT chemotherapy included headaches, nausea, and vomiting, with more severe complications such as myelotoxicity, disseminated intravascular coagulopathy, meningitis, and gastrointestinal toxicity reported in some cases.
CONCLUSIONS: LMD continues to be an uncommon complication associated with HGG with a poor prognosis. This article provides an overview of the presently available literature on IT chemotherapy for LMD secondary to HGG, and their respective treatment protocols with overall survival attributes. Additional research is warranted to ascertain how to maximize the potential efficacy of IT chemotherapy as a treatment option.

OBJECTIVE: To explore the impact of intrathecal pemetrexed (IP) on the survival of lung adenocarcinoma (LUAC) patients with leptomeningeal metastasis (LM).
METHODS: We analyzed patients with LUAC and LM who received systemic therapy after LM diagnosis at the Fujian Cancer Hospital between July 2018 and March 2022. Patients who underwent IP were assigned to the IP group; those without IP treatment were designated as the non-IP group. Propensity score matching (PSM) was performed between the two groups.
RESULTS: 165 patients were enrolled: 83 and 82 in the IP and non-IP groups, respectively. After 1:1 PSM, we included 114 patients in the matched cohort. Median overall survival (OS) was 13.2 months (95% CI 10.8-15.6 months) in the IP group versus 10.1 months (95% CI 5.3-14.9 months) in the non-IP group (P = 0.488). Only Eastern Cooperative Oncology Group Performance Status (ECOG PS) was confirmed as an independent predictor for OS in the matched cohort (hazard ratio (HR) 2.03; P = 0.023). Multivariate competing-risks analysis showed that IP significantly correlated with central nervous system-related death (HR 0.31; P = 0.046). When stratified by ECOG PS, IP improved survival in patients with poor ECOG PS (PS = 2) (14.3 months vs. 1.6 months; P = 0.003).
CONCLUSIONS: Intrathecal pemetrexed did not enhance OS for the entire LUAC patient with LM compared to non-intrathecal chemotherapy. However, it exhibited the potential to reduce the risk of central nervous system-related mortality and improve survival in patients with poor ECOG PS.

OBJECTIVE: Headaches are a common, oftentimes debilitating symptom in patients with leptomeningeal metastases.
RESULTS: The third edition of the International Classification of Headache Disorders provides a useful diagnostic framework for headaches secondary to leptomeningeal metastases based on the temporal relationship of headache with disease onset, change in headache severity in correlation with leptomeningeal disease burden, and accompanying neurologic signs such as cranial nerve palsies and encephalopathy. However, headaches in patients with leptomeningeal metastases can be further defined by a wide range of varying cancer- and treatment-related pathophysiologies, each requiring a tailored approach. A thorough review of the literature and expert opinion on five observed headache sub-classifications in patients with leptomeningeal metastases is provided, with attention to necessary diagnostic testing, recommended first-line treatments, and prevention strategies.