Brown, Paul D.

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 Background IDH-wild type (-wt) status is a prerequisite for the diagnosis of glioblastoma (GBM); however, IDH-wt gliomas with low-grade or anaplastic morphology have historically been excluded from GBM trials and may represent a distinct prognostic entity. While alkylating agent chemotherapy improves overall survival (OS) and progression-free survival (PFS) for IDH-wt GBM and also IDH-mutant gliomas, irrespective of grade, the benefit for IDH-wt diffuse histologic lower-grade gliomas is unclear. Methods We performed a meta-analysis of randomized clinical trials for World Health Organization (WHO) grades 2–3 gliomas (2009 to present) to determine the effect of alkylating chemotherapy on IDH-wt and -mutant gliomas using a random-effects model with inverse-variance pooling. Results We identified 6 trials with 1204 patients (430 IDH-wt, 774 IDH-mutant) that evaluated alkylating chemoradiotherapy versus radiotherapy alone, allowing us to perform an analysis focused on the value of adding alkylating chemotherapy to radiotherapy. For patients with IDH-wt tumors, alkylating chemotherapy added to radiotherapy was associated with improved PFS (HR:0.77 [95% CI: 0.62–0.97], P = .03) but not OS (HR:0.87 [95% CI: 0.64–1.18], P = .17). For patients with IDH-mutant tumors, alkylating chemotherapy added to radiotherapy improved both OS (HR:0.52 [95% CI: 0.42–0.64], P < .001) and PFS (HR = 0.47 [95% CI: 0.39–0.57], P < .001) compared to radiotherapy alone. The magnitude of benefit was similar for IDH-mutant gliomas with or without 1p19q-codeletion. Conclusions Alkylating chemotherapy reduces mortality by 48% and progression by 53% for patients with IDH-mutant gliomas. Optimal management of IDH-wt diffuse histologic lower-grade gliomas remains to be determined, as there is little evidence supporting an OS benefit from alkylating chemotherapy.

2008 Background: For non-small cell lung cancer (NSCLC) with brain metastases (BM) stereotactic radiosurgery (SRS) is the current preferred therapy. Due to frequent intracranial failures, there is a high unmet need for salvage therapies. Whole brain radiotherapy (WBRT) reduces intracranial failure but used less frequently due to cognitive consequences. Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell division and have shown improved survival and safety in patients with glioblastoma and metastatic NSCLC. Phase 3 METIS trial [NCT02831959] aimed to evaluate the efficacy and safety of TTFields therapy in NSCLC patients with BM treated with SRS, specifically in terms of lengthening time to intracranial progression without cognitive decline. Methods: Mutation negative (M-) NSCLC patients with 1–10 BM were randomized 1:1 to receive stereotactic radiosurgery (SRS) followed by Tumor Treating Fields (TTFields; 150 kHz) therapy with best supportive care (BSC) or SRS followed by BSC. Patients with Karnofsky Performance Status (KPS) ≥70, newly diagnosed with one inoperable or 2–10 supra-/infratentorial brain metastases suitable for SRS and receiving optimal extracranial disease therapy were included. Exclusions were prior WBRT and single operable or recurrent brain metastases. Primary endpoint was time to first intracranial progression (RANO-BM) based on cumulative risk. Patients were followed every two months until second intracranial progression. Cognition and patient quality of life (QoL) were evaluated. Results: Between July 2016 and September 2022, 298 patients were randomized. Baseline characteristics were balanced: median age was 63.5 (range 37-84) years, 37.6% females, majority of patients had a KPS ≥ 80, median time from initial NSCLC diagnosis was 1.8 months (range: 0.2-55.7), 77% had adenocarcinoma. Median treatment duration of TTFields was 16 weeks, with a median usage time of 67%. Primary endpoint, time to intracranial progression from SRS, was significantly prolonged with SRS followed by TTFields therapy with BSC vs. BSC alone arm (median of 21.9 vs. 11.3 months); HR=0.67 [0.48-0.93], p=0.02. TTFields-related AEs were mainly dermatological, and Grade ≤2. TTFields therapy also improved deterioration-free survival of global health status, physical functioning, and fatigue according to QoL, and did not negatively impact cognition. Conclusion: METIS study met its primary endpoint, demonstrating that TTFields therapy following SRS in mutation negative NSCLC patients with BM, significantly prolongs time to intracranial progression and could postpone WBRT, without QoL and cognition decline. Clinical trial information: NCT02831959 .

Mutations in isocitrate dehydrogenase (IDH) genes, an early step in the ontogeny of lower-grade gliomas, induce global epigenetic changes characterized by a hypermethylation phenotype and are critical to tumor classification, treatment decision making, and estimation of patient prognosis. The introduction of IDH inhibitors to block the oncogenic neomorphic function of the mutated protein has resulted in new therapeutic options for these patients. To appreciate the implications of these recent IDH inhibitor results, it is important to juxtapose historical outcomes with chemoradiotherapy. Herein, we rationally evaluate recent IDH inhibitor data within historical precedents to guide contemporary decisions regarding the role of observation, maximal safe resection, adjuvant therapies, and the import of patient and tumor variables. The biological underpinnings of the IDH pathway and the mechanisms, impact, and limitations of IDH inhibitors, the actual magnitude of tumor regression and patient benefit, and emergence of resistance pathways are presented to guide future trial development. Management in the current, molecularly defined era will require careful patient selection and risk factor assessment, followed by an open dialog about the results of studies such as INDIGO, as well as mature data from legacy trials, and a discussion about risk-versus-benefit for the choice of treatment, with multidisciplinary decision making as an absolute prerequisite.

Abstract Background Minimal clinically important differences (MCIDs) quantify the clinical relevance of quality of life results at the individual patient and group level. The aim of this study was to estimate the MCID for the Brief Fatigue Inventory (BFI) and the Worst and Usual Fatigue items in patients with brain or CNS cancer undergoing curative radiotherapy. Methods Data from a multi-site prospective registry was used. The MCID was calculated using distribution-based and anchor-based approaches. For the anchor-based approach, the fatigue item from the PROMIS-10 served as the anchor to determine if a patient improved, deteriorated, or had no change from baseline to end of treatment (EOT). We compared the unadjusted means on the BFI for the 3 groups to calculate the MCID. For the distribution-based approaches, we calculated the MCID as 0.5 SD of the scores and as 1.96 times the standard error of measurement. Results Three-hundred and fifty nine patients with brain or CNS tumors undergoing curative radiotherapy filled out the 9-item BFI at baseline and EOT. The MCID for the BFI was 1.33 (ranging from 0.99 to 1.70 across the approaches), 1.51 (ranging from 1.16 to 2.02) and 1.76 (ranging from 1.38 to 2.14) for the usual and worst fatigue items, respectively. Conclusions This study provides the MCID ranges for the BFI and Worst and Usual fatigue items, which will allow clinically meaningful conclusions to be drawn from BFI scores. These results can be used to select optimal treatments for patients with brain or CNS cancer or to interpret BFI scores from clinical trials.

AbstractMeningeal solitary fibrous tumors (SFT) are rare and have a high frequency of local recurrence and distant metastasis. In a cohort of 126 patients (57 female, 69 male; mean age at surgery 53.0 years) with pathologically confirmed meningeal SFTs with extended clinical follow‐up (median 9.9 years; range 15 days–43 years), we performed extensive molecular characterization including genome‐wide DNA methylation profiling (n = 80) and targeted TERT promoter mutation testing (n = 98). Associations were examined with NAB2::STAT6 fusion status (n = 101 cases; 51 = ex5‐7::ex16‐17, 26 = ex4::ex2‐3; 12 = ex2‐3::exANY/other and 12 = no fusion) and placed in the context of 2021 Central Nervous System (CNS) WHO grade. NAB2::STAT6 fusion breakpoints (fusion type) were significantly associated with metastasis‐free survival (MFS) (p = 0.03) and, on multivariate analysis, disease‐specific survival (DSS) when adjusting for CNS WHO grade (p = 0.03). DNA methylation profiling revealed three distinct clusters: Cluster 1 (n = 38), Cluster 2 (n = 22), and Cluster 3 (n = 20). Methylation clusters were significantly associated with fusion type (p < 0.001), with Cluster 2 harboring ex4::ex2‐3 fusion in 16 (of 20; 80.0%), nearly all TERT promoter mutations (7 of 8; 87.5%), and predominantly an “SFT” histologic phenotype (15 of 22; 68.2%). Clusters 1 and 3 were less distinct, both dominated by tumors having ex5‐7::ex16‐17 fusion (respectively, 25 of 33; 75.8%, and 12 of 18; 66.7%) and with variable histological phenotypes. Methylation clusters were significantly associated with MFS (p = 0.027), but not overall survival (OS). In summary, NAB2::STAT6 fusion type was significantly associated with MFS and DSS, suggesting that tumors with an ex5::ex16‐17 fusion may have inferior patient outcomes. Methylation clusters were significantly associated with fusion type, TERT promoter mutation status, histologic phenotype, and MFS.

Stereotactic radiosurgery (SRS) is an important weapon in the management of brain metastases. Single-fraction SRS is associated with local control rates ranging from approximately 70% to 100%, which are largely dependent on lesion and postoperative cavity size. The rates of local control and improved neurocognitive outcomes compared with conventional whole-brain radiation therapy have led to increased adoption of SRS in these settings. However, when treating larger targets and/or targets located in eloquent locations, the risk of normal tissue toxicity and adverse radiation effects within healthy brain tissue becomes significantly higher. Thus, hypofractionated SRS has become a widely adopted approach, which allows for the delivery of ablative doses of radiation while also minimizing the risk of toxicity. This approach has been studied in multiple retrospective reports in both the postoperative and intact settings. While there are no reported randomized data to date, there are trials underway evaluating this paradigm. In this article, we review the role of hypofractionated SRS in the management of brain metastases and emerging data that will serve to validate this treatment approach. Pertinent articles and references were obtained from a comprehensive search of PubMed/MEDLINE and clinicaltrials.gov.

Abstract Background This study aimed to determine whether proton craniospinal irradiation (CSI) decreased the dose to normal tissue and resulted in less toxicity than photon CSI for adult patients. Methods This single-institution retrospective analyzed differences in radiation doses, acute toxicity, and cost between proton and CSI for adult medulloblastoma patients. Results Of 39 total patients, 20 were treated with photon CSI prior to 2015, and 19 were treated with proton CSI thereafter. Median age was 28 years (range 18–66). The molecular subtype was most commonly sonic hedgehog (68%). Patients most commonly received 36 Gy CSI in 20 fractions with a boost to 54–55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to cochleae, lacrimal glands, lens, parotid glands, pharyngeal constrictors, esophagus, lungs, liver, and skin (all P &lt; .001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% versus 35%, P = .044) and decreased median weight loss during radiation (+1.0 versus –2.8 kg, P = .011). Weight loss was associated with acute hospitalization (P = .009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At the last follow-up, 5 photon patients had died (2 of progressive disease, 3 without recurrence ages 41–63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. Conclusions This study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.