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The incidence of brain metastases has markedly increased in the past 20 years owing to progress in the treatment of malignant solid tumours, earlier diagnosis by MRI and an ageing population. Although local therapies remain the mainstay of treatment for many patients with brain metastases, a growing number of systemic options are now available and/or are under active investigation. HER2-targeted therapies (lapatinib, neratinib, tucatinib and trastuzumab emtansine), alone or in combination, yield a number of intracranial responses in patients with HER2-positive breast cancer brain metastases. New inhibitors are being investigated in brain metastases from ER-positive or triple-negative breast cancer. Several generations of EGFR and ALK inhibitors have shown activity on brain metastases from EGFR and ALK mutant non-small-cell lung cancer. Immune-checkpoint inhibitors (ICIs) hold promise in patients with non-small-cell lung cancer without druggable mutations and in patients with triple-negative breast cancer. The survival of patients with brain metastases from melanoma has substantially improved after the advent of BRAF inhibitors and ICIs (ipilimumab, nivolumab and pembrolizumab). The combination of targeted agents or ICIs with stereotactic radiosurgery could further improve the response rates and survival but the risk of radiation necrosis should be monitored. Advanced neuroimaging and liquid biopsy will hopefully improve response evaluation.This Review outlines the advances of molecular treatment of brain metastases from non-small-cell lung cancer, breast cancer and melanoma. Substantial improvements in survival have been achieved in patients with molecular subgroups whose alterations can be targeted with specific molecular compounds.

The presence of barriers, such as the blood–brain barrier (BBB) and brain–tumor barrier (BTB), limits the penetration of antineoplastic drugs into the brain, resulting in poor response to treatments. Many techniques have been developed to overcome the presence of these barriers, including direct injections of substances by intranasal or intrathecal routes, chemical modification of drugs or constituents of BBB, inhibition of efflux pumps, physical disruption of BBB by radiofrequency electromagnetic radiation (EMP), laser-induced thermal therapy (LITT), focused ultrasounds (FUS) combined with microbubbles and convection enhanced delivery (CED). However, most of these strategies have been tested only in preclinical models or in phase 1–2 trials, and none of them have been approved for treatment of brain tumors yet. Concerning the treatment of brain metastases, many molecules have been developed in the last years with a better penetration across BBB (new generation tyrosine kinase inhibitors like osimertinib for non-small-cell lung carcinoma and neratinib/tucatinib for breast cancer), resulting in better progression-free survival and overall survival compared to older molecules. Promising studies concerning neural stem cells, CAR-T (chimeric antigen receptors) strategies and immunotherapy with checkpoint inhibitors are ongoing.

Purpose of ReviewTo review state of art and relevant advances in the molecular genetics and management of ependymomas of children and adults.Recent FindingsEpendymomas may occur either in the brain or in the spinal cord. Compared with intracranial ependymomas, spinal ependymomas are less frequent and exhibit a better prognosis. The new WHO classification of CNS tumors of 2021 has subdivided ependymomas into different histomolecular subgroups with different outcome. The majority of studies have shown a major impact of extent of resection; thus, a complete resection must be performed, whenever possible, at first surgery or at reoperation. Conformal radiotherapy is recommended for grade 3 or incompletely resected grade II tumors. Proton therapy is increasingly employed especially in children to reduce the risk of neurocognitive and endocrine sequelae. Craniospinal irradiation is reserved for metastatic disease. Chemotherapy is not useful as primary treatment and is commonly employed as salvage treatment for patients failing surgery and radiotherapy.SummaryStandard treatments are still the mainstay of treatment: the discovery of new druggable pathways will hopefully increase the therapeutic armamentarium in the near future.

This guideline provides recommendations for diagnostic and therapeutic procedures for patients with malignant gliomas. We differentiate evidence-based standards from reasonable options or non-evidence-based measures that should no longer be considered. The recommendations herein should provide a framework and assurance for the choice of diagnostic procedures and therapeutic measures and aim to reduce complications from unnecessary treatment and cost. The guideline contributes to a critical appreciation of concurrent drugs with a focus on the controlled use of anticonvulsants and steroids. It should serve as a guideline for all professionals involved in the diagnostics and care of glioma patients and also as a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in Europe. Implementation of the recommendations summarised here will need interdisciplinary structures of care for patients with brain tumours and structured processes of diagnostic and therapeutic procedures.

Although meningiomas are the most common intracranial tumours, the level of evidence to provide recommendations for the diagnosis and treatment of meningiomas is low compared with other tumours such as high-grade gliomas. The meningioma task force of the European Association of Neuro-Oncology (EANO) assessed the scientific literature and composed a framework of the best possible evidence-based recommendations for health professionals. The provisional diagnosis of meningioma is mainly made by MRI. Definitive diagnosis, including histological classification, grading, and molecular profiling, requires a surgical procedure to obtain tumour tissue. Therefore, in many elderly patients, observation is the best therapeutic option. If therapy is deemed necessary, the standard treatment is gross total surgical resection including the involved dura. As an alternative, radiosurgery can be done for small tumours, or fractionated radiotherapy in large or previously treated tumours. Treatment concepts combining surgery and radiosurgery or fractionated radiotherapy, which enable treatment of the complete tumour volume with low morbidity, are being developed. Pharmacotherapy for meningiomas has remained largely experimental. However, antiangiogenic drugs, peptide receptor radionuclide therapy, and targeted agents are promising candidates for future pharmacological approaches to treat refractory meningiomas across all WHO grades.

An estimated 20% of all patients with cancer will develop brain metastases, with the majority of brain metastases occurring in those with lung, breast and colorectal cancers, melanoma or renal cell carcinoma. Brain metastases are thought to occur via seeding of circulating tumour cells into the brain microvasculature; within this unique microenvironment, tumour growth is promoted and the penetration of systemic medical therapies is limited. Development of brain metastases remains a substantial contributor to overall cancer mortality in patients with advanced-stage cancer because prognosis remains poor despite multimodal treatments and advances in systemic therapies, which include a combination of surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapies. Thus, interest abounds in understanding the mechanisms that drive brain metastases so that they can be targeted with preventive therapeutic strategies and in understanding the molecular characteristics of brain metastases relative to the primary tumour so that they can inform targeted therapy selection. Increased molecular understanding of the disease will also drive continued development of novel immunotherapies and targeted therapies that have higher bioavailability beyond the blood–tumour barrier and drive advances in radiotherapies and minimally invasive surgical techniques. As these discoveries and innovations move from the realm of basic science to preclinical and clinical applications, future outcomes for patients with brain metastases are almost certain to improve. An estimated 20% of all patients with cancer will develop brain metastases, with the majority of brain metastases occurring in those with lung and breast cancer and melanoma. This Primer describes the mechanisms by which cancer cells migrate to the brain and the key advances necessary to improve the prognosis for patients with brain metastases.

Glioblastoma is a highly vascularised tumour and there are few treatment options after disease recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases. We aimed to assess the efficacy and safety of regorafenib in the treatment of recurrent glioblastoma. REGOMA is a randomised, multicentre, open-label phase 2 trial done in ten centres in Italy. Eligible patients (aged ≥18 years) with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after surgery followed by radiotherapy and temozolomide chemoradiotherapy were randomly assigned (1:1) by a web-based system, stratified by centre and surgery at recurrence (yes vs no), to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m2 once every 6 weeks until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02926222, and is currently in follow-up. Between Nov 27, 2015, and Feb 23, 2017, 124 patients were screened and 119 eligible patients were randomly assigned to receive regorafenib (n=59) or lomustine (n=60). Median follow-up was 15·4 months (IQR 13·8–18·1). At the analysis cutoff date, 99 (83%) of 119 patients had died: 42 (71%) of 59 in the regorafenib group and 57 (95%) of 60 in the lomustine group. Overall survival was significantly improved in the regorafenib group compared with the lomustine group, with a median overall survival of 7·4 months (95% CI 5·8–12·0) in the regorafenib group and 5·6 months (4·7–7·3) in the lomustine group (hazard ratio 0·50, 95% CI 0·33–0·75; log-rank p=0·0009). Grade 3–4 treatment-related adverse events occurred in 33 (56%) of 59 patients treated with regorafenib and 24 (40%) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand–foot skin reaction, increased lipase, and blood bilirubin increased (in six [10%] of 59 patients each). In the lomustine group, the most common grade 3 or 4 adverse events were decreased platelet count (eight [13%] of 60 patients), decreased lymphocyte count (eight [13%]), and neutropenia (seven [12%]). No death was considered by the investigators to be drug related. REGOMA showed an encouraging overall survival benefit of regorafenib in recurrent glioblastoma. This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study. Veneto Institute of Oncology and Bayer Italy.

Systemic therapy for brain metastases (BM) is quickly moving from conventional cytotoxic chemotherapy toward targeted therapies, that allow a disruption of driver molecular pathways. The discovery of actionable driver mutations has led to the development of an impressive number of tyrosine kinase inhibitors (TKIs), that target the epidermal growth factor receptor (EGFR) mutations, anaplastic-lymphoma-kinase (ALK) rearrangements, and other rare molecular alterations in patients bearing metastatic non-small cell lung cancer (NSCLC) in the brain, with remarkable results in terms of intracranial disease control and overall survival. Moreover, these drugs may delay the use of local therapies, such as stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT). New drugs with higher molecular specificity and ability to cross the CNS barriers (BBB, BTB and blood-CSF) are being developed. Two major issues are related to targeted therapies. First, the emergence of a resistance is a common event, and a deeper understanding of molecular pathways that are involved is critical for the successful development of effective new targeted agents. Second, an early detection of tumor progression is of utmost importance to avoid the prolongation of an ineffective therapy while changing to another drug. In order to monitor over time the treatment to targeted therapies, liquid biopsy, that allows the detection in biofluids of either circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) or exosomes, is increasingly employed in clinical trials: with respect to BM the monitoring of both blood and CSF is necessary. Also, radiomics is being developed to predict the mutational status of the BM on MRI.For patients without druggable mutations or who do not respond to targeted agents, immunotherapy with checkpoint inhibitors is increasingly employed, alone or in combination with radiotherapy. Pseudoprogression after immunotherapy alone maybe a challenge for several months after the start of treatment, and the same is true for radionecrosis after the combination of immunotherapy and SRS. In this regard, the value of advanced MRI techniques and PET imaging for a better distinction of pseudoprogression/radionecrosis and true tumor progression is promising, but needs validation in large prospective datasets. Last, a new frontier in the near future will be chemoprevention (primary and secondary), but we need to identify among solid tumors those subgroups of patients with a higher risk of relapsing into the brain and novel drugs, active on either neoplastic or normal cells of the microenvironment, that are cooperating in the invasion of brain tissue.

Leptomeningeal metastases (LM) from solid tumors represent an unmet need of increasing importance due to an early use of MRI for diagnosis and improvement of outcome of some molecular subgroups following targeted agents and immunotherapy. In this review, we first discussed factors limiting the efficacy of targeted agents in LM, such as the molecular divergence between primary tumors and CNS lesions and CNS barriers at the level of the normal brain, brain tumors and CSF. Further, we reviewed pathogenesis and experimental models and modalities, such as MRI (with RANO and ESO/ESMO criteria), CSF cytology and liquid biopsy, to improve diagnosis and monitoring following therapy. Efficacy and limitations of targeted therapies for LM from EGFR-mutant and ALK-rearranged NSCLC, HER2-positive breast cancer and BRAF-mutated melanomas are reported, including the use of intrathecal administration or modification of traditional cytotoxic compounds. The efficacy of checkpoint inhibitors in LM from non-druggable tumors, in particular triple-negative breast cancer, is discussed. Last, we focused on some recent techniques to improve drug delivery.

The value of interdisciplinary teams in improving outcomes and quality of care of patients with brain metastases remains uncertain, partly due to the lack of consensus on key indicators to evaluate interprofessional care. We aimed to obtain expert consensus across disciplines on indicators that evaluate the quality and value of brain metastases care. A steering committee of key opinion leaders curated relevant outcomes and process indicators from a literature review and a stakeholder needs assessment, and an international panel of physicians rated the outcomes and process indicators using a modified Delphi method. After three rounds, a consensus was reached on 29 indicators encompassing brain-directed oncological treatment, surgery, whole-brain radiotherapy, stereotactic radiosurgery, supportive or palliative care, and interdisciplinary team care. The Brain Metastases Quality-of-Care measure reflects the value and quality of brain metastases team-based care according to treatment modality and provides a benchmark of care for this under-studied patient population. The adoption, implementation, and sustainability of this set of indicators could help address the need expressed by patients with cancer, caregivers, and clinicians for more coordinated care across inpatient, outpatient, home, community, and tertiary academic settings.