Elsevier

The Lancet

Volume 392, Issue 10145, 4–10 August 2018, Pages 432-446
The Lancet

Seminar
Primary brain tumours in adults

https://doi.org/10.1016/S0140-6736(18)30990-5Get rights and content

Summary

Primary CNS tumours refer to a heterogeneous group of tumours arising from cells within the CNS, and can be benign or malignant. Malignant primary brain tumours remain among the most difficult cancers to treat, with a 5 year overall survival no greater than 35%. The most common malignant primary brain tumours in adults are gliomas. Recent advances in molecular biology have improved understanding of glioma pathogenesis, and several clinically significant genetic alterations have been described. A number of these (IDH, 1p/19q codeletion, H3 Lys27Met, and RELA-fusion) are now combined with histology in the revised 2016 WHO classification of CNS tumours. It is likely that understanding such molecular alterations will contribute to the diagnosis, grading, and treatment of brain tumours. This progress in genomics, along with significant advances in cancer and CNS immunology, has defined a new era in neuro-oncology and holds promise for diagntic and therapeutic improvement. The challenge at present is to translate these advances into effective treatments. Current efforts are focused on developing molecular targeted therapies, immunotherapies, gene therapies, and novel drug-delivery technologies. Results with single-agent therapies have been disappointing so far, and combination therapies seem to be required to achieve a broad and durable antitumour response. Biomarker-targeted clinical trials could improve efficiencies of therapeutic development.

Introduction

Primary brain tumours refer to a heterogeneous group of tumours arising from cells within the CNS. Gliomas represent 75% of malignant primary brain tumours in adults.1 Gliomas are tumours of neuroectodermal origin arising from glial or precursor cells, and include astrocytomas, oligodendrogliomas, and ependymomas. Their classification has undergone major restructuring in the 2016 version of the WHO classification of CNS tumours,2 with a subsequent effect on diagnostic criteria, diagnostic testing approaches, grading, prognosis, and treatment planning. The incorporation of both molecular and histological parameters into this revised classification, along with progress in genomics and in cancer and CNS immunology, has defined a new era in neuro-oncology.

This Seminar emphasises key changes in the current classification of gliomas, and also explores the main molecular markers and their clinical significance. We also review current standard-of-care management for the main adult gliomas subtypes, and provide a clinically focused summary of practice-changing clinical trials. Finally, we provide an overview of emerging treatments for gliomas.

Section snippets

Clinical presentation

Patients with primary brain tumours can present with focal (ie, related to a specific location in the brain) or generalised symptoms over days to weeks, or months to years, depending on the speed of growth and location of the tumour. Tumours can also be found by brain imaging that has been done for unrelated purposes.

Tumours in some functional areas of the brain will cause more obvious focal neurological deficits than in other areas, and tend to be discovered sooner on imaging. Frontal lobe

Epidemiology

The 2017 Central Brain Tumor Registry of the United States report provides a detailed discussion of brain tumour epidemiology.1 Primary brain tumours account for about 2% of all cancers, with an overall annual incidence of 22 per 100 000 population.1 Incidence increases with advancing age, and is highest in individuals older than 85 years. Nearly 80 000 new cases of primary brain tumours are expected in 2018 in the USA, of which one-third will be malignant.1 Meningiomas are the most common

Prognostic factors

Prognostic factors vary considerably by tumour type. Younger age, high performance status, lower tumour grade, and greater extent of resection are favourable prognostic factors for most adult primary brain tumours. Over the past decade, molecular genetic alterations have been recognised as more powerful prognostic and predictive markers than histological appearance alone (table 1).6, 14, 44, 45

Risk factors

Less than 5% of primary brain tumours are due to genetic predisposition syndromes (table 2), and most patients do not have identifiable risk factors. Ionising radiation is the only other uncontested risk factor for primary brain tumours.52, 53 No other environmental exposure or behaviour has been unequivocally identified.54 Of particular interest has been the potential association between cell phone use and risk of developing a brain tumour. Despite multiple large studies, no conclusive

Diagnostic investigations

In a patient with a suspected brain tumour, MRI with gadolinium is the investigation of choice (appendix). Additionally, multimodal MRI such as diffusion-weighted imaging and diffusion tensor imaging, MR perfusion, and MR spectroscopy are used to better characterise the tumour cellularity, vascularity, and metabolism, respectively, and can help distinguish tumour from non-neoplastic processes, including treatment effect.6, 62, 63, 64 CNS staging with craniospinal MRI is performed in selected

Surgical management

The initial treatment for most primary brain tumours is maximal safe resection, with goals of achieving an accurate histological diagnosis, establishing the tumour's molecular genotype, improving the quality of life, and increasing survival. Although there are no randomised controlled trials regarding the benefit of the extent of resection, the available evidence suggests that maximal safe resection improves functional status and reduces mortality in both low-grade65 and high-grade gliomas.6, 66

Upfront management by tumour type

In this Seminar, a treatment overview is provided for most frequent adult primary brain tumours (Figure 1, Figure 2). For additional details, the reader is referred to the National Comprehensive Cancer Network (NCCN)6 and the European Association For Neuro-Oncology (EANO) guidelines,7, 74 as well as referenced articles. Every effort should be made for a referral to a centre of excellence, which will afford both clinical trial participation6 and improved outcomes.

Management at recurrence

Pilocytic astrocytoma can progress as long as 25 years after surgery, especially when subtotally resected, but typically maintains its grade.76 Conversely, most diffuse low-grade gliomas and nearly all high-grade gliomas will eventually recur, and often transform into a higher grade.6 In the absence of positive phase 3 trials or level 1 evidence to guide treatment at progression or recurrence, all the above-mentioned options are used alone or in combination, and clinical trial participation is

Medical management

This section provides a brief overview on commonly encountered medical complications in glioma patients. For expanded discussion, the reader is referred to the NCCN6 and EANO guidelines.7, 74, 112

Future directions

Despite substantial progress over the past decade in revealing the molecular underpinnings of primary brain tumours, there remain few effective therapies. There are many possible reasons for this frustrating outcome: poor drug blood-brain barrier penetration, redundancy of intracellular signalling pathways, tumour molecular heterogeneity, and lack of validated biomarkers. Current experimental strategies include immunotherapy, targeted therapy, gene therapy, and novel drug-delivery technologies,

Outstanding research questions

Primary brain tumours remain difficult and challenging diseases to manage despite substantial progress in understanding their genesis. Further work is needed to understand the role of glioma stem cells in the origin of primary brain tumours and how the different modes of therapy may be used in such a setting. Even though very few trials have progressed to phase 3, recent advancements in immunotherapy, targeted and combination therapy show promise and provide hope. In addition, further analysis

Conclusion

Treatments and better outcomes for primary brain tumours have long lagged behind those of other tumours. However, a new era in neuro-oncology has emerged, with major advances in both cancer and CNS immunology, and progress in genomics. These rapid advances have created more therapeutic opportunities than ever before in neuro-oncology. It is likely that combinatorial regimens will be required to achieve a broad and durable antitumour benefit, and new advances in cell engineering technologies and

Search strategy and selection criteria

This Seminar is based on studies published during the past 5 years, although classic papers have also been cited. We searched PubMed and Embase for papers published between January, 2012, and March, 2018, using the search terms: “brain tumour”, “glioblastoma”, “glioma”, “astrocytoma”, “oligodendroglioma”, “ependymoma”, and “pilocytic astrocytoma” in combination with the terms: “risk factors”, “molecular”, “investigation”, “management”, “surgical resection”, “drug therapy”, “clinical trial”,

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