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.

Data demonstrate improved survival with proton craniospinal irradiation (CSI) over involved field radiation therapy for leptomeningeal disease (LMD). It is unknown how photon CSI compares in the treatment of LMD. We report our institution's real-world experience using proton versus photon CSI for LMD. We performed a retrospective review of LMD patients treated with photon or proton CSI from January 2021 to February 2024. All histologies were included. Patient characteristics and complete blood counts were collected before and after CSI. The primary endpoint was serious cytopenia likely caused by CSI. The median overall survival was estimated using the Kaplan-Meier method. Thirty-six patients with LMD treated with CSI (27 proton and 9 photon) were included. Across all major cell lines (hemoglobin, platelets, leukocytes, neutrophils, and lymphocytes), the rate of serious (grade 3 or higher) cytopenia likely caused by CSI was not different between the proton and photon groups (p > .21). The median overall survival in the proton and photon groups was 3.0 months and 1.7 months, respectively (hazard ratio, 1.49; p = .47). In a single-institutional experience treating LMD, acute cytopenias likely caused by CSI were not different between proton and photon CSI across all major cell lines. Survival was also similar between modalities; therefore, photon CSI may be a safe, efficacious option for LMD.

Background: High-grade gliomas (HGGs), particularly glioblastoma (GBM), are associated with exceptionally high mortality and inevitable recurrence. In considering novel treatment options for these devastating diseases, immunotherapies represent promising candidates. Immunotherapies have demonstrated efficacy for several advanced tumors outside the central nervous system, highlighting a potential role for these agents in treating HGGs. However, multiple challenges to immunotherapy efficacy have tempered therapeutic benefit in practice, including local and systemic immunosuppression, intratumoral heterogeneity, and various mechanisms of intrinsic and acquired resistance. In the past 30 years, diverse immunotherapeutic subclasses have been assessed for benefit against HGGs. Methods: We performed a PubMed search for randomized clinical trials performed within the last 30 years evaluating the following immunotherapy agents for high-grade gliomas: immune checkpoint inhibitors, vaccines, oncologic viruses, cytokines, and CAR T-cells. The present review offers a critical analysis of key pre-clinical and clinical trials that have shaped the immunotherapy landscape for high-grade gliomas over the past two decades. Results/Conclusions: Across the different immunotherapeutic methods and modalities explored thus far, a recurring theme emerges: while therapeutic strategies with a compelling conceptual basis are continually under development and even demonstrate a benefit in preclinical and early-phase trials, larger and later-phase trials consistently fail to produce concordantly significant outcomes. To date, no large-scale clinical trial has demonstrated a benefit of sufficient consequence to change practice. Continued critical appraisal of the strengths and pitfalls of prior investigative work, optimization of treatment development and delivery, and innovative approaches to combination therapy design will collectively be integral to future therapeutic advancement.

BackgroundPatients with medulloblastoma require craniospinal irradiation (CSI) to optimize disease control; however, cranial irradiation is associated with significant morbidity. We sought to develop a novel target volume (CTV_2340 cGy) and explore dosimetric benefits to minimize cognitive toxicity. MethodsWe conducted a literature review to confirm patterns of failure for average risk medulloblastoma to develop the CTV_2340 definition approach. Five patients (ages 4-16 years) were identified and proton and photon plans were generated for the new CTV_2340. Planning target goals included V100% ≥ 95% (the entire volume receiving at least 95% prescription dose) and V98% ≥ 97%. Proton planning included 3D robust optimization +/- 2mm and +/- 2% range uncertainties. Photon plans included a 1mm planning target volume. ResultsMedulloblastoma principally recurs in the ventricular system, periventricular region, cortical surface, or posterior fossa, supporting potential omission of remaining non-target-brain (NTB, e.g. white matter tracts, thalami). The novel CTV_2340 included these regions with a 1mm brain expansion. All proton-based plans achieved appropriate target coverage. Median whole brain volumes were 1317.1cc (range: 1116.0-1442.1), reflecting brain size over the age spectrum. Median NTB was 15% of the brain volume (9-31%), whereas the hippocampi were <1%. Median NTB_V12Gy and V18Gy were: 91.7% (79.3-92.3) and 70.2% (59.8-78.2). Median NTB_minimum and NTB_mean were: 2.1 Gy (0.8-2.9) and 19.4 Gy (18.0-20.2). CTV_2340 overlapped with the hippocampi, limiting hippocampal sparing (median V18 Gy 99.1%). Photon-based planning showed inferior target coverage with minimal sparing. ConclusionsThis study introduces a strategic approach to reduce radiotherapy-related neurotoxicity in medulloblastoma through proton-based sparing of critical brain regions. Multi-institutional studies are warranted to further advance this approach.