Frechette, K.M.

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.

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.

Abstract Immune checkpoint inhibitors (ICIs) have demonstrated remarkable response rates in relapsed or refractory Hodgkin lymphoma (HL). Still, most patients eventually progress. Patterns of progression after ICIs are not well described and are essential to defining the role of local therapies in combination with ICIs. We identified patients who received ICIs for HL between 2013 and 2022. Fludeoxyglucose-18 positron emission tomography (FDG-PET) before initiating ICI and at progression on/after ICI were reviewed, and areas of active HL were recorded. An exploratory analysis of treatable progression included patients with ≤5 sites of disease on pre-ICI FDG-PET and progression only at pre-ICI sites. Ninety patients were identified; 69 had complete records, and of these, 32 (52%) had relapsed at ICI initiation, 17 (25%) were refractory, and 16 (23%) received ICI as first-line therapy. Forty-five of 69 patients had ≤5 sites of disease (limited) on pre-ICI FDG-PET. Patients with >5 sites of disease had a higher risk of progression, and every site of disease >5 sites conferred an additional 1.2x higher chance of progression. At a median follow-up of 4.0 years, 41 of 69 patients had progressed on/after ICIs (cumulative incidence 66.4%), and of these, 22 of 41 patients progressed only at pre-ICI sites (cumulative incidence 39.4%). In an exploratory analysis, the cumulative incidence of a treatable progression among 45 patients with limited disease was 34%. The cumulative incidence of any progression among this cohort was 58.9%. More than one-third of patients with limited disease before ICIs experienced progression only at pre-ICI sites of disease. These patients could be candidates for radiation during or after ICIs.

Abstract BACKGROUND Leptomeningeal disease (LMD) is a devastating complication of cancer with median overall survival (OS) of 3-6 months following diagnosis. Proton craniospinal irradiation (pCSI) is a novel treatment option for LMD, permitting whole neuroaxis treatment with tolerable toxicity and improved efficacy compared to conventional photon whole brain radiation therapy and as needed focal spine radiotherapy. Despite this, patients experience progression and succumb to LMD. Addition of systemic therapy to pCSI may improve outcomes. METHODS In this single institution retrospective case series, we report feasibility of combination treatment with pCSI and immune checkpoint inhibitor (ICI) in patients with LMD from solid tumors. RESULTS Three patients were treated with pCSI (30 Gy in 10 fractions) and ICI. The first patient developed LMD related to large cell neuroendocrine carcinoma of lung primary, diagnosed by imaging and cytology, having previously undergone resection and stereotactic radiosurgery for brain metastases. Clinical and radiographic improvement was noted following pCSI, bevacizumab, and pembrolizumab therapy. Patient experienced disease progression and passed away only after ICI was held due to hypophysitis, with 6-month OS. The second patient developed LMD related to BRAF V600E mutant melanoma, diagnosed by imaging and cytology, having previously undergone ICI and BRAF-targeted therapy. Following pCSI, relatlimab, nivolumab, and BRAF-targeted therapy, the patient remains alive 7 months after LMD diagnosis despite radiographic progression treated with carboplatin, paclitaxel, intrathecal IL-2, ipilimumab, and bevacizumab. The third developed LMD related to BRAF-wildtype melanoma, diagnosed by imaging, having previously received ICI. Patient underwent pCSI followed by ipilimumab and nivolumab, progression-free 5 months after LMD diagnosis. CONCLUSION Addition of systemic therapy to pCSI is feasible for patients with LMD. Combination of ICI and pCSI may confer additional survival benefit, even among patients with prior exposure to ICI. These initial promising results warrant prospective evaluation.

Abstract PURPOSE For large brain metastases, it is unknown whether single fraction stereotactic radiosurgery (sSRS) or multi-fraction stereotactic radiosurgery (fSRS) is optimal. We aimed to compare rates of local progression and necrosis between sSRS and fSRS for large brain metastases. METHODS Patients with intact or resected brain metastases with a target volume ≥ 4.2 cc (corresponding to a diameter ≥ 2 cm) treated with Gamma Knife (GK) or linear accelerator-based SRS from 2014-2022 were included in this retrospective review. RESULTS A total of 343 large brain metastases in 276 patients were included; 171 lesions were treated with sSRS (96% with GK) and 172 lesions with fSRS (100% with linear accelerator). Median lesion volume was 19.8 cc and 8.4 cc for fSRS and sSRS, respectively. Resection was performed prior to SRS in 228 (66%), with the remaining 115 metastases treated intact. There was no difference in rate of local progression between sSRS versus fSRS, or between resected versus intact targets (p >0.8 for both). Cumulative incidence of local progression (with death as a competing risk) at 1 and 3 years for patients receiving sSRS was 24% and 30%, respectively, compared to 22% and 34% for fSRS. FSRS was associated with significantly higher rates of necrosis than sSRS (HR 5.58, 2.38-13.08, p < 0.001). This association remained significant after controlling for target volume. Cumulative incidence of necrosis (with death as a competing risk) at 1 and 3 years for patients receiving sSRS was 1% and 3%, respectively, compared to 10% and 18% for fSRS. Necrosis rates were significantly higher with fSRS for both intact and resected targets (P < 0.02 for both). CONCLUSION While local control for large resected or intact brain metastases appears similar after sSRS or fSRS, this retrospective study shows higher rates of necrosis after fSRS. Prospective validation is needed.

ABSTRACT Introduction Proton craniospinal irradiation (pCSI) is a treatment option for leptomeningeal disease (LMD), which permits whole neuroaxis treatment while minimizing toxicity. Despite this, patients inevitably experience progression. Adding systemic therapy to pCSI may improve outcomes. Methods In this single-institution retrospective case series, we present the feasibility of treatment with pCSI (30Gy, 10 fractions) and an immune checkpoint inhibitor (ICI) in two sequential patients with LMD from melanoma. Results The first patient developed LMD related to BRAF V600E-mutant melanoma after prior ICI and BRAF-targeted therapy. After pCSI with concurrent nivolumab, the addition of relatlimab, and BRAF-targeted therapy, he remained alive 7 months after LMD diagnosis despite central nervous system progression. The second patient developed LMD related to BRAF-wildtype melanoma after up-front ICI. He received pCSI with concurrent ipilimumab and nivolumab, then nivolumab maintenance. Though therapy was held for ICI hepatitis, the patient remained progression-free 5 months after LMD diagnosis. Conclusion Adding an ICI to pCSI is feasible for patients with LMD and demonstrates a tolerable toxicity profile. While prospective evaluation is ultimately warranted, pCSI with ICI may confer survival benefits, even after prior ICI.

Abstract PURPOSE To compare outcomes of adults with high-risk grade II oligodendroglioma treated with adjuvant radiotherapy plus adjunctive TMZ versus PCV. METHODS We queried a multi-institutional database from the Cleveland Clinic and Mayo Clinic of 158 adults with WHO grade II glioma who were high-risk (age > 40 and/or subtotal-resection [STR]) and underwent adjuvant chemoradiation (TMZ or PCV) between 1997–2017. We included patients with oligodendroglioma by 1p/19q-codeletion or traditional histopathology. Fisher’s exact test was used to associate factors with chemotherapy group. The log-rank test was used to compare OS and PFS by chemotherapy group and clinical characteristics. RESULTS 52 patients were included with a median follow-up of 44 months (range, 3–259). Median age was 44 (range, 22–73), 49 (94%) underwent STR, and 28 (54%) were male. Presenting symptoms were seizure in 35 (67%) patients, sensory in 14 (27%), and motor in 8 (15%). Oligodendroglioma classification was by 1p/19q-codeletion in 27 (52%) and traditional histopathology in 25 (48%) patients. Median radiation dose was 54 Gy (range, 45–60). Chemotherapy was TMZ in 34 (65%) patients and PCV in 18 (35%). Patients who were older (P=0.003), lacked seizures (P=0.03), or had motor symptoms (P=0.04) were more likely to receive TMZ. Median OS was 223 months (95% CI, 181-not estimable) and median PFS was 118 months (95% CI, 69–223). Treatment with TMZ versus PCV was not associated with OS (median 186 vs. 223 months, respectively; P=0.71) or PFS (median 110 vs. 131 months, respectively; P=0.19). Age >40 (P=0.009) and motor symptoms (P=0.027) were associated with adverse OS. Presence of motor symptoms was associated with worse PFS (P=0.008). CONCLUSION There was no statistically significant difference in OS or PFS between adjunctive TMZ versus PCV for adult high-risk grade II oligodendroglioma. A larger cohort with longer follow-up will provide additional insight.