IDH inhibition in gliomas: from preclinical models to clinical trials.

Gliomas are the most common malignant primary brain tumours in adults and cannot usually be cured with standard cancer treatments. Gliomas show intratumoural and intertumoural heterogeneity at the histological and molecular levels, and they frequently contain mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene. IDH-mutant adult-type diffuse gliomas are subdivided into grade 2, 3 or 4 IDH-mutant astrocytomas and grade 2 or 3 IDH-mutant, 1p19q-codeleted oligodendrogliomas. The product of the mutated IDH genes, D-2-hydroxyglutarate (D-2-HG), induces global DNA hypermethylation and interferes with immunity, leading to stimulation of tumour growth. Selective inhibitors of mutant IDH, such as ivosidenib and vorasidenib, have been shown to reduce D-2-HG levels and induce cellular differentiation in preclinical models and to induce MRI-detectable responses in early clinical trials. The phase III INDIGO trial has demonstrated superiority of vorasidenib, a brain-penetrant pan-mutant IDH inhibitor, over placebo in people with non-enhancing grade 2 IDH-mutant gliomas following surgery. In this Review, we describe the pathway of development of IDH inhibitors in IDH-mutant low-grade gliomas from preclinical models to clinical trials. We discuss the practice-changing implications of the INDIGO trial and consider new avenues of investigation in the field of IDH-mutant gliomas.

Association of Clinical, Tumor, and Treatment Characteristics With Seizure Control in Patients With IDH1/2-Mutant Lower-Grade Glioma.

BACKGROUND AND OBJECTIVES: Patients with IDH1/2-mutant lower-grade glioma have a high frequency of seizures. We aimed to investigate the correlations between seizures and tumor/patient characteristics and the impact of surgery and adjuvant treatments (AT) on seizure control along the disease trajectory. METHODS: We retrospectively included patients with IDH1/2-mutant lower-grade glioma who underwent surgery at the neurosurgery divisions of the University of Turin and Milan and were treated at the Division of Neuro-Oncology of Turin. Inclusion criteria were a diagnosis according to the 2021 WHO Classification and presentation with seizures; exclusion criteria were presence of CDKN2A/B homozygous deletion, intense/ring contrast enhancement on MRI at presentation, and small tissue biopsy. We evaluated seizure freedom for 2 months after surgery, 6 months from starting observation or AT, at recurrence, and for 6 months after treatments of recurrence. RESULTS: We included 150 patients. There were 77 (51%) and 31 (21%) patients with IDH-mutant/1p19q-codeleted grade 2 and 3 oligodendroglioma and 30 (20%) and 12 (8%) with IDH-mutant grade 2 and 3 astrocytoma, respectively. Total resection was accomplished in 68 (45%). Seventy-five patients (50%) received AT while the remaining 75 were observed with MRI. After 6 months after AT, 28 of 29 patients (96.5%) displayed seizure reduction, 5 of 28 (18%) being seizure-free. 66 of 124 patients (53%) had seizures at recurrence. After 6 months after second-line treatments, 60 of 66 patients (91%) had seizure reduction, 11 (17%) being seizure-free. In multivariable analyses, grade 3 histology positively correlated with seizure freedom at 2 months after surgery (OR 3.5, 1.4-8.9, p = 0.008), 6 months after AT (OR 9.0, 1.5-54.9, p = 0.017), and 6 months after treatment of recurrence (OR 4.9, 1.5-16.5, p = 0.009). Adjuvant radiotherapy reduced seizures at recurrence in a univariate analysis (OR 0.14, 0.03-0.7, p = 0.020). Patients with seizure freedom after surgery and AT displayed longer progression-free survival (PFS) (65, 24.5-105, vs 48 months, 32-63.5, p = 0.037). DISCUSSION: This study analyzed seizure control in patients with IDH1/2-mutant lower-grade glioma across multiple time points. Grade 3 correlated with better seizure control throughout the entire disease trajectory, and seizure freedom after surgery and AT correlated with a longer PFS regardless of tumor grade. These results could serve as an external control arm in clinical trials evaluating the efficacy on seizures of antitumor agents in patients with IDH-mutant lower-grade glioma.

Liquid biopsy for improving diagnosis and monitoring of CNS lymphomas: A RANO review.

BACKGROUND: The utility of liquid biopsies is well documented in several extracranial and intracranial (brain/leptomeningeal metastases, gliomas) tumors. METHODS: The RANO (Response Assessment in Neuro-Oncology) group has set up a multidisciplinary Task Force to critically review the role of blood and cerebrospinal fluid (CSF)-liquid biopsy in CNS lymphomas, with a main focus on primary central nervous system lymphomas (PCNSL). RESULTS: Several clinical applications are suggested: diagnosis of PCNSL in critical settings (elderly or frail patients, deep locations, and steroid responsiveness), definition of minimal residual disease, early indication of tumor response or relapse following treatments, and prediction of outcome. CONCLUSIONS: Thus far, no clinically validated circulating biomarkers for managing both primary and secondary CNS lymphomas exist. There is need of standardization of biofluid collection, choice of analytes, and type of technique to perform the molecular analysis. The various assays should be evaluated through well-organized central testing within clinical trials.

Challenges, Limitations and Pitfalls of PET and Advanced MRI in Patients with Brain Tumors - A Report of the PET/RANO Group.

Brain tumor diagnostics have significantly evolved with the use of PET and advanced MRI techniques. In addition to anatomical MRI, these modalities may provide valuable information for several clinical applications such as differential diagnosis, delineation of tumor extent, prognostication, differentiation between tumor relapse and treatment-related changes, and the evaluation of response to anticancer therapy. In particular, joint recommendations of the RANO group, the EANO, and major European and American Nuclear Medicine societies highlighted that the additional clinical value of radiolabeled amino acids compared to anatomical MRI alone is outstanding and that its widespread clinical use should be supported. For advanced MRI and its steadily increasing use in clinical practice, the Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition provided more recently an updated acquisition protocol for the widely used dynamic susceptibility contrast perfusion MRI. Besides amino acid PET and perfusion MRI, other PET tracers and advanced MRI techniques (e.g., MR spectroscopy) are of considerable clinical interest and are increasingly integrated into everyday clinical practice. Nevertheless, these modalities have shortcomings which should be considered in clinical routine. This comprehensive review provides an overview of potential challenges, limitations and pitfalls associated with PET imaging and advanced MRI techniques in patients with gliomas or brain metastases. Despite these issues, PET imaging and advanced MRI techniques continue to play an indispensable role in brain tumor management. Acknowledging and mitigating these challenges through interdisciplinary collaboration, standardized protocols, and continuous innovation will further enhance the utility of these modalities in guiding optimal patient care.

The 2022 European postgraduate (residency) programme in neurology in a historical and international perspective.

BACKGROUND AND PURPOSE: Neurology residency programmes, which were first established at the beginning of the 20th century, have become mandatory all over Europe in the last 40-50 years. The first European Training Requirements in Neurology (ETRN) were published in 2005 and first updated in 2016. This paper reports the most recent revisions of the ETRN. METHODS: Members of the EAN board performed an in depth revision of the ETNR 2016-version, which was reviewed by members of the European Board and Section of Neurology of the UEMS, the Education and Scientific Panels, the Resident and Research Fellow Section and the Board of the EAN, as well as the presidents of the 47 European National Societies. RESULTS: The new (2022) ETRN suggest a 5-year training subdivided in three phases: a first phase (2 years) of general neurology training, a second phase (2 years) of training in neurophysiology/neurological subspecialties and a third phase (1 year) to expand clinical training (e.g., in other neurodisciplines) or for research (path for clinical neuroscientist). The necessary theoretical and clinical competences as well as learning objectives in diagnostic tests have been updated, are newly organized in four levels and include 19 neurological subspecialties. Finally, the new ETRN require, in addition to a programme director, a team of clinician-educators who regularly review the resident's progress. The 2022 update of the ETRN reflects emerging requirements for the practice of neurology and contributes to the international standardization of training necessary for the increasing needs of residents and specialists across Europe.

The early recognition and diagnosis of neoplastic meningitis.

INTRODUCTION: The diagnosis and monitoring of leptomeningeal metastases (LM) from solid tumors are challenging, and the combination of neurological symptoms, MRI findings, and cerebrospinal fluid (CSF) cytology does not always allow to achieve a definitive diagnosis. AREAS COVERED: This review summarizes the studies that have investigated CSF liquid biopsy to improve the initial diagnosis of LM in case the CSF cytology is negative or only suspicious for tumor cells, and monitoring of tumor response following targeted therapies or immunotherapy. In this regard, the early detection of LM recurrence and the development of resistant mutations are critical issues. Moreover, the early identification of subgroups of patients with a higher risk of LM progression, as well as the correlation of LM burden with survival, are discussed. EXPERT OPINION: There is an urgent need of prospective studies to monitor longitudinally LM using CSF liquid biopsy and investigate the role of CTC, ctDNA or novel assays. The optimal setting for the longitudinal CSF and blood collection can be clinical trials focused on the molecular diagnosis of LM as well as the response and monitoring following targeted agents.

European Cancer Organisation Essential Requirements for Quality Cancer Care: Adult glioma.

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCCs) are explanations of the organisation and actions necessary to provide high-quality care to patients with a specific cancer type. They are compiled by a working group of European experts representing disciplines involved in cancer care, and provide oncology teams, patients, policymakers and managers with an overview of the essential requirements in any healthcare system. The focus here is on adult glioma. Gliomas make up approximately 80% of all primary malignant brain tumours. They are highly diverse and patients can face a unique cognitive, physical and psychosocial burden, so personalised treatments and support are essential. However, management of gliomas is currently very heterogeneous across Europe and there are only few formally-designated comprehensive cancer centres with brain tumour programmes. To address this, the ERQCC glioma expert group proposes frameworks and recommendations for high quality care, from diagnosis to treatment and survivorship. Wherever possible, glioma patients should be treated from diagnosis onwards in high volume neurosurgical or neuro-oncology centres. Multidisciplinary team working and collaboration is essential if patients' length and quality of life are to be optimised.

Neurotoxicity from Old and New Radiation Treatments for Brain Tumors.

Research regarding the mechanisms of brain damage following radiation treatments for brain tumors has increased over the years, thus providing a deeper insight into the pathobiological mechanisms and suggesting new approaches to minimize this damage. This review has discussed the different factors that are known to influence the risk of damage to the brain (mainly cognitive disturbances) from radiation. These include patient and tumor characteristics, the use of whole-brain radiotherapy versus particle therapy (protons, carbon ions), and stereotactic radiotherapy in various modalities. Additionally, biological mechanisms behind neuroprotection have been elucidated.

The impact of survivorship bias in glioblastoma research.

Despite advances in the therapy of Central Nervous System (CNS) malignancies, treatment of glioblastoma (GB) poses significant challenges due to GB resistance and high recurrence rates following post-operative radio-chemotherapy. The majority of prognostic and predictive GB biomarkers are currently developed using tumour samples obtained through surgical interventions. However, the selection criteria adopted by different neurosurgeons to determine which cases are suitable for surgery make operated patients not representative of all GB cases. Particularly, geriatric and frail individuals are excluded from surgical consideration in some cancer centers. Such selection generates a survival (or selection) bias that introduces limitations, rendering the patients or data chosen for downstream analyses not representative of the entire community. In this review, we discuss the implication of survivorship bias on current and novel biomarkers for patient selection, stratification, therapy, and outcome analyses.

Long-term survival with IDH wildtype glioblastoma: first results from the ETERNITY Brain Tumor Funders' Collaborative Consortium (EORTC 1419).

BACKGROUND: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. METHODS: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumours, prognostic factors were analysed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich. RESULTS: At the database lock of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 incompletely characterised) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumours with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Median overall survival was 9.9 years (95% confidence interval [95% CI] 7.9-11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p < 0.001) and had a high rate (48.8%) of MGMT promoter-unmethylated tumours. CONCLUSIONS: Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Patients without relapse often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma.

Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma.

BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas. METHODS: In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed. RESULTS: A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo. CONCLUSIONS: In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).

Intrathecal trastuzumab versus alternate routes of delivery for HER2-targeted therapies in patients with HER2+ breast cancer leptomeningeal metastases.

BACKGROUND: Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant, adjuvant, and metastatic settings, including for parenchymal brain metastases, their efficacy for patients with LM has not been studied in a randomized controlled trial. However, several single-armed prospective studies, case series and case reports have studied oral, intravenous, or intrathecally administered HER2-targeted therapy regimens for patients with HER2+ BC LM. METHODS: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BC LM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (intrathecal or intravenous), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine and trastuzumab-deruxtecan. The primary endpoint was overall survival (OS), with CNS-specific progression-free survival (PFS) as a secondary endpoint. RESULTS: 7780 abstracts were screened, identifying 45 publications with 208 patients, corresponding to 275 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable and multivariable analyses, we observed no significant difference in OS and CNS-specific PFS between intrathecal trastuzumab compared to oral or intravenous administration of HER2-targeted therapy. Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors. In a cohort of 15 patients, treatment with trastuzumab-deruxtecan was associated with prolonged OS compared to other HER2-targeted therapies and compared to trastuzumab-emtansine. CONCLUSIONS: The results of this meta-analysis, comprising the limited data available, suggest that intrathecal administration of HER2-targeted therapy for patients with HER2+ BC LM confers no additional benefit over oral and/or IV treatment regimens. Although the number of patients receiving trastuzumab deruxtecan in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies.

Antiangiogenic Therapy for Malignant Brain Tumors: Does It Still Matter?

PURPOSE OF REVIEW: To summarize the mechanisms of tumor angiogenesis and resistance to antiangiogenic therapy, and the influence on tumor microenvironment. RECENT FINDINGS: Several clinical trials have investigated the activity of anti-VEGF monoclonal antibodies and tyrosine kinase inhibitors in glioblastoma, shedding the light on their limitations in terms of disease control and survival. We have outlined the mechanisms of resistance to antiangiogenic therapy, including vessel co-option, hypoxic signaling in response to vessel destruction, modulation of glioma stem cells, and trafficking of tumor-associated macrophages in tumor microenvironment. Moreover, novel generation of antiangiogenic compounds for glioblastoma, including small interfering RNAs and nanoparticles, as a delivery vehicle, could enhance selectivity and reduce side effects of treatments. There is still a rationale for the use of antiangiogenic therapy, but a better understanding of vascular co-option, vascular mimicry, and dynamic relationships between immunosuppressive microenvironment and blood vessel destruction is crucial to develop next-generation antiangiogenic compounds.

Brain Metastasis from HER2-Positive Breast Cancer: An Evolving Landscape.

Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate with ability to cross the blood-tumor barrier and activity on brain metastases. To test the activity of new drugs, patient-derived xenograft models from human brain metastases and phase 0 and window-of-opportunity trials are of utmost importance. See related article by Kabraji et al., p. 174.

European Association of Neuro-Oncology (EANO) guidelines for treatment of primary central nervous system lymphoma (PCNSL).

The management of primary central nervous system (PCNSL) is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the limited number of controlled studies available. In 2021, given recent advances and the publication of practice-changing randomized trials, the European Association of Neuro-Oncology (EANO) created a multidisciplinary task force to update the previously published evidence-based guidelines for immunocompetent adult patients with PCNSL and added a section on immunosuppressed patients. The guideline provides consensus considerations and recommendations for the treatment of PCNSL, including intraocular manifestations and specific management of the elderly. The main changes from the previous guideline include strengthened evidence for the consolidation with ASCT in first-line treatment, prospectively assessed chemotherapy combinations for both young and elderly patients, clarification of the role of rituximab even though the data remain inconclusive, of the role of new agents, and the incorporation of immunosuppressed patients and primary ocular lymphoma. The guideline should aid the clinicians in everyday practice and decision making and serve as a basis for future research in the field.

Observational real-life study on regorafenib in recurrent glioblastoma: does dose reduction reduce toxicity while maintaining the efficacy?

PURPOSE: In the phase 2 REGOMA trial, regorafenib improved overall survival, as compared with lomustine, in glioblastoma (GBM) patients at first progression after chemoradiation. Recently, some real-life trials showed similar impact on survival but a higher rate of adverse events than in REGOMA, thus raising concerns over tolerability. The aim of this study was to assess the efficacy and tolerability of a lower intensity regorafenib regimen. PATIENTS AND METHODS: Regorafenib daily dose was gradually increased from 80 to 160 mg across the first 2 cycles. Progression-free survival (PFS) and overall survival (OS) were defined as time from regorafenib initiation and disease progression or death. RESULTS: Sixty-six GBM patients were included. Median age was 60.0 years. Median PFS and OS following regorafenib were 2.7 and 7.1 months, respectively. Best RANO response to regorafenib were partial response (PR) in 10 (15.1%), stable disease in 17 (25.8%), and progressive disease in 39 (59.1%) patients. Forty-six (69.7%) patients presented adverse events of any grade, and 21 (31.8%) grade 3-4 toxicity. In a multivariable analysis, higher age and absence of MGMTp methylation were significantly associated with poorer disease control after regorafenib. CONCLUSIONS: Our study is the largest observational real-life study on the use of regorafenib. Our lower intensity regimen proved as effective as the standard 160 mg daily schedule (mPFS and mOS being 2.7 vs 2.0 months and 7.1 vs 7.4 months in our study vs REGOMA, respectively). Moreover, we observed a higher rate of PRs as compared with REGOMA (15.0% vs 3.0%).

Newly diagnosed Glioblastoma Multiforme (GBM) during COVID-19 pandemic: changes in therapeutic approach to minimize in-hospital SARS-COV-2 contagion in pre-vaccine era.

COVID-19 pandemic revolutionized the way in which cancer patients are treated worldwide. Regarding neuro-oncological patients, usually considered frail and with lower life-expectancy in respect to other oncological patients, the international scientific community had to urgently reorganize the treatment approach in order to minimize the risk of in-hospital contagious. For GBM patients, adjuvant treatments have been evaluated with even much more attention with regard to the expected efficacy. As a consequence, an hypofractioned radiotherapy regimen has been preferred in order to reduce the daily hospital accesses and, especially in pMGMT unmethylated patients, chemotherapy with Temozolomide was avoided. Here, we made a comprehensive evaluation of the neurooncological community suggestions regarding GBM treatment in the pre-vaccine era of COVID-19 pandemic.

EANO - EURACAN - SNO Guidelines on circumscribed astrocytic gliomas, glioneuronal, and neuronal tumors.

In the new WHO 2021 Classification of CNS Tumors the chapter "Circumscribed astrocytic gliomas, glioneuronal and neuronal tumors" encompasses several different rare tumor entities, which occur more frequently in children, adolescents, and young adults. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is low particularly for adult patients, and draw recommendations accordingly. Tumor diagnosis, based on WHO 2021, is primarily performed using conventional histological techniques; however, a molecular workup is important for differential diagnosis, in particular, DNA methylation profiling for the definitive classification of histologically unresolved cases. Molecular factors are increasing of prognostic and predictive importance. MRI finding are non-specific, but for some tumors are characteristic and suggestive. Gross total resection, when feasible, is the most important treatment in terms of prolonging survival and achieving long-term seizure control. Conformal radiotherapy should be considered in grade 3 and incompletely resected grade 2 tumors. In recurrent tumors reoperation and radiotherapy, including stereotactic radiotherapy, can be useful. Targeted therapies may be used in selected patients: BRAF and MEK inhibitors in pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas when BRAF altered, and mTOR inhibitor everolimus in subependymal giant cells astrocytomas. Sequencing to identify molecular targets is advocated for diagnostic clarification and to direct potential targeted therapies.

Investigational PET tracers in neuro-oncology-What's on the horizon? A report of the PET/RANO group.

Many studies in patients with brain tumors evaluating innovative PET tracers have been published in recent years, and the initial results are promising. Here, the Response Assessment in Neuro-Oncology (RANO) PET working group provides an overview of the literature on novel investigational PET tracers for brain tumor patients. Furthermore, newer indications of more established PET tracers for the evaluation of glucose metabolism, amino acid transport, hypoxia, cell proliferation, and others are also discussed. Based on the preliminary findings, these novel investigational PET tracers should be further evaluated considering their promising potential. In particular, novel PET probes for imaging of translocator protein and somatostatin receptor overexpression as well as for immune system reactions appear to be of additional clinical value for tumor delineation and therapy monitoring. Progress in developing these radiotracers may contribute to improving brain tumor diagnostics and advancing clinical translational research.