Primary brain tumours in adults

Seminar

Primary brain tumours in adults Sarah Lapointe, Arie Perry, Nicholas A Butowski

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 mol­ ecular 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.

Brain tumours

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 tumours might cause weakness or dys­ phasia; parietal lobe tumours might cause numbness,

hemineglect, or spatial disorientation; and tumours involving the optic rad­iations anywhere in the temporal, parietal, or occipital lobe might cause visual field defects. Conversely, tumours located in the prefrontal lobe, temporal lobe, or corpus callosum often result in subtler cognitive dysfunctions such as personality changes, mood disorders, and short-term memory deficits. Infratentorial tumours can cause a combination of cranial-nerve palsies, cerebellar dysfunction, and long-tract signs. Brain tumours can also present with generalised symptoms and signs, not specific to one anatomic location. For example, 50–80% of patients might pre­ sent with seizures,3,4 about 30% with headaches,5 and 15% with symptoms of increased intracranial pressure, such as progressive headaches worse at night, morning nausea and vomiting, drowsiness, blurred vision from papilloedema, and horizontal diplopia from cranial nerve VI palsy.5

Published Online July 27, 2018 http://dx.doi.org/10.1016/ S0140-6736(18)30990-5 Department of Neurological Surgery (S Lapointe MD), Division of Neuropathology, Department of Pathology (Prof A Perry MD), Department of Neurological Surgery (N A Butowski MD), University of California, San Francisco, CA, USA Correspondence to: Dr Nicholas A Butowski, Department of Neurological Surgery, University of California, San Francisco, CA, USA [email protected]

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”, “chemotherapy”, “temozolomide”, “radiotherapy”, “complications”, “epilepsy”, “immunotherapy”, and “targeted therapy”. Additional relevant articles were identified from the reference lists of articles identified by this search. Articles were screened for relevance by title and abstract, then selected for inclusion based on the related contribution to the topics discussed herein.

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

1

Seminar

Differential diagnosis

See Online for appendix

The differential diagnosis for a brain mass depends on patient age, risk factors for infection, the presence of another cancer, and imaging characteristics. Principal differential categories include metastases, infections, inflammatory disorders, and vascular lesions (appendix). In a solitary ring-enhancing lesion, a sharply contoured lesion with normal overlying cortex favours metastasis, whereas a more ill-defined lesion with expanded adjacent cortex favours high-grade glioma, and a lesion with centrally reduced diffusion favours abscess.

Pathological classification Brain tumours are classified according to the WHO CNS tumours grading system.2 Until recently, primary CNS tumours were defined on the basis of histological criteria and assigned a grade (from I to IV). In 2016, the classification was revised from the 2007 classification to incorporate signature molecular genetic alterations to the classic histology. This combined phenotypic and genotypic classification generated new integrated diagnoses, where the histopathological name is followed

by the genetic features (eg, glioblastoma, IDH-wildtype; panel). In case of discordant results from histology and molecular genetic features, the genotype is considered more informative than the histological phenotype.2 The use of molecular parameters improves diagnostic objectivity and accuracy, and will probably result in more precise determination of prognosis and treatment response.

Gliomas Previous to the 2016 WHO update,2 all astrocytic tumours were grouped together. As of 2016, gliomas are sep­ arated into circumscribed gliomas (WHO grade I) and diffusely infiltrating gliomas (WHO grades II–IV; whether astrocytic or oligodendroglial) based on their pattern of growth and the presence or not of IDH mutation (panel). Circumscribed gliomas represent tumours mostly regarded as benign and curable by complete resection. Circumscribed gliomas do not have an IDH mutation and have frequent BRAF mutations and fusions (eg, pilocytic astrocytoma and pleomorphic xanthoastrocytoma).2

Panel: Simplified WHO 2016 classification of selected neuroepithelial tissue tumours*2 (with addition of newly recognised 2016 entities) Other astrocytic tumours (often referred as “circumscribed gliomas”) WHO I • Pilocytic astrocytoma

Ependymal tumours WHO I • Subependymoma • Myxopapillary ependymoma

WHO II • Pleomorphic xanthoastrocytoma

WHO II • Ependymoma

WHO III • Anaplastic pleomorphic xanthoastrocytoma†

WHO II or III • Ependymoma, RELA fusion-positive

Diffuse astrocytic and oligodendroglial tumours (often referred as “diffuse gliomas”) WHO II • Diffuse astrocytoma, IDH-mutant† • Diffuse astrocytoma, IDH-wildtype† • Diffuse astrocytoma, NOS† • Oligodendroglioma, IDH-mutant and 1p/19q-codeleted† • Oligodendroglioma, NOS†

WHO III • Anaplastic ependymoma

WHO III (anaplastic) • Anaplastic astrocytoma, IDH-mutant† • Anaplastic astrocytoma, IDH-wildtype† • Anaplastic astrocytoma, NOS† • Anaplastic oligodendroglioma, IDH-mutant and 1p/19q codeleted† • Anaplastic oligodendroglioma, NOS† WHO IV • Glioblastoma, IDH-wildtype† • Glioblastoma, IDH-mutant† • Glioblastoma, NOS† • Diffuse midline glioma, H3 K27M-mutant†

2

Neuronal and mixed neuronal-glial tumours • Diffuse leptomeningeal glioneural tumour‡ WHO I • Dysembryoplastic neuroepithelial tumour • Ganglioglioma • Gangliocytoma • Dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos) WHO III • Anaplastic ganglioglioma This panel has been abridged and modified from the WHO 2016 classification of selected neuroepithelial tissue tumours,2 with the deletion of former entity (gliomatosis cerebri) and variants (protoplasmic and fibrillary astrocytoma variants, cellular ependymoma variant). Gliomatosis cerebri no longer represents a distinct entity in the 2016 WHO classification; it is now considered a clinicoradiological pattern that can be encountered in any diffuse glioma. IDH=isocitrate dehydrogenase. NOS=not otherwise specified. RELA=reticuloendotheliosis viral oncogene homologue A. *Other neuroepithelial tissue tumours are included (tumours of choroid plexus, tumours of the pineal region, tumour of the sellar region, embryonal tumours, germ cell tumours, and tumours of the cranial and paraspinal nerves) and can be found elsewhere.2 †Newly recognised 2016 entities. ‡Because of the limited patient numbers reported so far, this new entity has not yet been assigned a distinct WHO grade.2

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

Seminar

Conversely, diffuse gliomas are almost never cured by resection alone, are graded using histopathological criteria, and are now classified according to diagnostic molecular markers. Histologically, grade II (low grade) diffuse astrocytomas show nuclear atypia, grade III (anaplastic) display increased mitotic activity, and grade IV (glioblastomas) show additional micro­vascular proliferation, necrosis, or both. In the 2016 classification, grades II–III gliomas are further stratified into three diagnostic and prognostic subgroups based on their IDH, ATRX, and 1p/19q status (figure 1).14,15 Most grade II–III gliomas harbour a key driver mutation in the IDH gene, and have characteristic TP53 and ATRX mutations;2 these gliomas are called diffuse astrocytoma, IDH-mutant (figure 1). In grades II–III gliomas harbouring IDH1 mutation but no ATRX mutation, 1p/19q codeletion status assess­ ment is required to distinguish astrocytomas from oligodendrogliomas.2,16 Although several observational studies6,7,16–19 have shown a promising role for TERT promoter mutation in predicting clinical outcome among grade II–III gliomas with the same IDH status and among glioblastomas independently of their IDH status, its prognostic impact remains controversial. Described below are the most commonly used molecular analyses for gliomas.

IDH Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations are thought to be an early event of glio­ magenesis, and are more commonly found in lower grade gliomas (>70% grades II–III astrocytomas; 100% oligodendrogliomas) than in glioblastomas, of which only 10% are referred to as secondary glio­ blastoma (defined clinically when arising from a lower grade astrocytoma) or glioblastoma, IDH-mutant (defined molecularly).10,18 Diffuse gliomas harbouring IDH1/2 mut­ations are associated with a better prognosis than diffuse gliomas, IDH-wildtype.2,20

1p/19q Codeletion of chromosomes 1p and 19q results from a non-balanced centromeric translocation t(1:19)(q10:p10).21 This codeletion, combined with IDH mutation, is now required for the diagnosis of oligodendroglioma, IDH-mutant and 1p/19q codeleted.11,16 1p/19q codeletion confers a favourable prognosis among diffuse gliomas and is predictive of an increased response to alkylating chemotherapy.2,10,21,22–24

H3 Lys27Met Mutations in the genes encoding histone proteins H3.3 (H3F3A) or H3.1 (HIST1H3B) resulting in lysine to methionine substitution at amino acid 27 (Lys27Met or K27M)25–27 molecularly defines the novel entity of diffuse mid­line glioma, H3 Lys27Met-mutant, WHO grade IV.11 H3 Lys27Met mutation is mutually exclusive with IDH

mutation, and has been suggested to be an early event of gliomagenesis.28–30 In children, these tumours commonly arise in the pons, whereas they more com­ monly involve thalamus or spinal cord in young adults.31 Among all diffuse gliomas, and within diffuse midline gliomas in general, the H3 Lys27Met-mutant tumours portend the worst prognosis (2 year survival <10%).2 They are considered WHO grade IV even if their histology otherwise appears low-grade or anaplastic.2 Among diffuse midline gliomas, H3 Lys27Met-mutant, those harbouring the H3.3 mutation have been proposed to portend a worse prognosis than those with the H3.1 mutation, although additional research is needed.32 In the setting of IDH-wildtype diffuse gliomas arising in midline CNS structures, H3 Lys27Met must be assessed by immunohistochemistry or sequen­cing. No predictive value has yet been identified for this mutation.

MGMT O⁶-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein involved in repairing damage that has been induced by alkylating agents such as temozolomide. Methylation of the MGMT promoter (MGMTp) silences the MGMT gene and reduces the ability of tumour cells to repair such damage. MGMTp methylation predicts benefit from alkylating chemo­therapies in glioblastoma patients,2,33,34 including elderly patients.35–37 However, its testing generally does not impact treatment as alkylating chemotherapy is the standard of care for all glioblastomas. MGMTp methy­lation also confers a favourable prognosis to both anaplastic astrocytomas20,22 and glioblastomas.2,33,34,38 MGMTp methylation is common in glioblastomas (30–50% of primary, IDH-wildtype, glioblastoma) and in oligodendrogliomas (>90%), but less common in lower grade astrocytomas.11,39

BRAF B-raf is a protein kinase regulating the RAS-RAFMEK-ERK cellular signalling pathway. BRAF alter­ ations, such as BRAFV600E mutation or KIAA1549-BRAF fusion, activate that pathway, and ultimately result in tumour growth and maintenance.40 BRAFV600E mutation is most commonly found in circumscribed gliomas, such as pleomorphic xanthoastrocytoma (60–80%),41 dys­ embryoplastic neuroepithelial tumours (30%),6 ganglio­­ gliomas (25%),36 and pilocytic astrocytomas (5–15%),41 but can also be found in about half of IDH-wildtype epithelioid glioblastomas.31,41 KIAA1549-BRAF fusion is almost exclusive to pilocytic astrocytomas,42 found in about 75% of those, and predict an indolent course.40,41

Ependymomas Ependymal tumours are of neuroectodermal origin, like other gliomas. The 2016 WHO classification mainly uses histological features to subdivide ependymal tu­ mours in 3 grades (I–II–III) and five distinct entities, with the addition of the new entity ependymoma, RELA

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

3

Seminar

fusion-positive (panel). Grade I ependymal tumours are defined on histopathology alone. However, accu­ rate histological distinction of grades II and III is chal­ lenging and has an inconsistent prognostic role. In 2017, an international consensus delineated nine

molecular ependymoma subgroups characterised by distinct epigenetic and genetic alter­ations, across different CNS locations and ages; this molecular strat­ification seems to reflect prognosis more precisely than histology alone, especially among grades II–III ependymomas (figure 2).43

Surgery

For all suspected glial tumours in adults Maximal safe resection Histopathology 1. Pattern of growth 2. WHO grade (for diffuse gliomas) I - Cellularity II - Atypia III - Mitotic activity IV - Endothelial proliferation and/or necrosis

Molecular/cytogenetic (based on location and age) 1. IHC for: IDH1 R132H + ATRX +/– H3K27M (if midline location) 2. If IDH1 R132H negative and <55 years: iDH-gene sequencing‡ 3. If IDH-mutant and ATRX retained: 1p/19q

Circumscribed gliomas

Diffuse gliomas

(I, II, III)

(II, III, IV)

IDH-wildtype (wt)

H3Lys27Met-wt§ BRAF alterations

IDH-mutant (mt)

ATRX-wt (retained)* TP53-wt (negative)*

IDH-wildtype (wt)

ATRX-mt (loss)* TP53-mt (positive)*

H3k27M-wt* 7p+, 10q–* TERTp-mt*

H3k27M-mt

Post-operative

1p/19q codeletion Integrated WHO diagnosis If genetic testing not done or inconclusive: • Diffuse astrocytoma, NOS • Oligodendroglioma, NOS • Glioblastoma, NOS Upfront management (NCCN 2017 & EANO 2017)

• GG, PA - I • PXA - II • GG, PXA - III

Oligodendroglioma, IDH-mt and 1p/19q codeleted, II or III

• Diffuse astrocytoma, IDH-mt, II or III • Secondary GBM, IDH-mt, IV

• Diffuse astrocytoma, IDH-wt, II or III • Primary GBM, IDH-wt, IV

• Diffuse midline glioma, H3k27M-mt, IV

Observation (PA)

II In selected patients¶ • Observation • (Chemotherapy alone) II-III • RT + PCV • (RT/TMZ + TMZ)

II In selected patients • Observation • (Chemotherapy alone) II-III • RT/TMZ + TMZ • (RT + PCV)

RT/TMZ + TMZ (some would argue for RT alone if MGMT unmethylated but not supported by prospective data*)

RT/TMZ + TMZ

Fair prognosis II (RTOG 9802) >12 years† III (RTOG 9402) >14 years (EORTC 26951) >14 years

Intermediate prognosis II (RTOG 9802) >13 years (WHO 2016) >10 years III (RTOG 9402) >2 years (WHO 2016) 3–5 years IV (WHO 2016) 2–6 years

Bad prognosis II (RTOG 9802) 5 years IV (WHO 2016) 1·3 years

Worst prognosis (Karremann, 2018) 1 year

Consider clinical trials

Surveillance MRI • Grade II: every 3–6 months x 5 year, then every year • Grades III–IV: every 2–4 months x 3 years, then every 6 months Median overall survival (From studies designed in the pre-molecular era)

4

Unclear

Best prognosis

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

Seminar

C11orf95 and RELA gene fusion is found in more than 70% of supratentorial ependymomas and confers a poor prognosis.43 This RELA fusion activates the NF-kB path­ way, resulting in uncontrolled tumour growth.

individuals, with the exception of meningiomas, pituitary tumours, and craniopharyngiomas, which are more com­ mon in African-Americans.1 Malignant primary brain tumours have an average annual mortality rate of 4·32 per 100 000 population, repre­senting more than 14 500 deaths every year in the USA, with an average 5-year survival of 35%. However, survival varies considerably when stratified by patient age, tumour type, and molecular features (table 1).1

Epidemiology

Prognostic factors

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 non-malignant primary brain tumours, followed by pituitary and nerve sheath tumours. Gliomas account for 75% of malignant brain tumours, and of these, more than half are glioblastomas (figure 3).1 The incidence of primary brain tumours varies with age, sex, and ethnic origin. Malignant brain tumours, such as gliomas, lymphomas, embryonal, and germ cell tumours, tend to occur slightly more frequently in men. However, brain tumours occur more frequently in women than in men generally, especially meningiomas and pituitary tumours. For all primary brain tumours for both sexes, incidence is higher in white than in African-American

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

In the next decade, molecular subgrouping or single molecular markers are expected to substantially impact clinical management and risk stratification processes.

RELA fusion

Figure 1: Simplified diagnostic decision-tree for gliomas All the information contained in this flow-chart has been adapted from the 2016 WHO Classification,2 the 2018 NCCN guidelines,6 the 2017 EANO guidelines,7 the phase 3 randomised trials RTOG 9802,8 RTOG 9402,9 EORTC 26951,10 WHO 2016,11 and the retrospective analysis on 62 paediatric H3 Lys27Met-mutant gliomas from Karremann, 2018.12 It should be noted that all these phase 3 trials had post-hoc molecular analyses. Treatments in parenthesis are considered acceptable options by the NCCN and EANO guidelines. IDH=Isocitrate dehydrogenase. ATRX=Alpha thalassaemia/mental retardation syndrome X. NOS=not otherwise specified. GBM=glioblastoma. NCCN=National Comprehensive Cancer Network. EANO=European Association of Neuro-Oncology. BRAF=B-raf proto-oncogene, serine/threonine kinase. GG=ganglioglioma. PA=pilocytic astrocytoma. PXA=pleomorphic xanthoastrocytoma. TP53=tumour protein p53. PCV=procarbazine, CCNU (lomustine) and vincristine. H3 Lys27Met=mutation causing replacement of lysine by methionine in aminoacid 27 of histone 3·1 or 3·3. *Not required for the diagnosis. Although ATRX mutation and 1p/19q codeletion are nearly mutually exclusive, and less than 3% of tumours with ATRX loss exhibit 1p/19q codeletion,10 1p/19q codeletion testing is required for the WHO diagnosis of oligodendroglioma. †Extrapolated from the overall survival table for oligodendroglioma.8 ‡If IDH1 R132H immunohistochemistry is negative and patient is over 55 years old, there is <1% chance of finding a rarer IDH mutation. §=this is a generality; there are now rare case reports of pilocytic astrocytoma or ganglioglioma with H3 Lys27Met mutation. ¶Low-risk diffuse gliomas WHO grade II patients are usually neurologically intact patients, status post gross total resection of an IDH-mutant +/– 1p/19q codeleted tumour.13 ||In patients with poor performance status (KPS <60), either hypofractionated radiation therapy alone, temozolomide alone in those harbouring the MGMT methylation, or best supportive care can be offered.

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 causative role for radiofrequency electromagnetic fields (RF-EMF), including cell phone use, has been established for brain tumours.55,56 Nonetheless, cumulative evidence suggests a very slight increased risk of glioma with longterm (>10 years) mobile phone use,57–59 and RF-EMF were classified by the WHO and International Agency for Research on Cancer as possibly carcinogenic to human beings in 2011,60 and were upgraded to probably carcino­ genic in 2015.61 Still, this association remains controversial, and additional research is needed.

Diagnostic investigations In a patient with a suspected brain tumour, MRI with gadolinium is the investigation of choice (appendix). Add­ itionally, 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, res­ pectively, and can help distinguish tumour from nonneoplastic processes, including treatment effect.6,62–64 CNS staging with craniospinal MRI is performed in selected cases. Whenever a brain metastasis is suspected, a systemic cancer screening with a careful clinical examination, and at least a chest-abdomen CT should be done.37 The incidence of brain metastases is about 10 times that of primary brain tumours in adults and as many as 30% of adults with systemic cancer will develop brain metastasis.6

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

5

Seminar

On their first post-radiation MRI, about 30% of glio­ blastoma patients, most commonly those with MGMTp methylation, will experience a transient in­ crease in enhancement within the irradiation field that will subside over time, called pseudoprogression. Advanced MRI techniques have shown promise in diff­ erentiating tumour progression from treatment effect, but additional work is necessary to standardise these approaches.6

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

Surgery

For all suspected ependymal tumours in adults Maximal safe resection (consider re-surgery if STR) Histopathology 1 - Cell type 2 - WHO grade I - Subependymoma or MPE II - Ependymoma III - Ependymoma with brisk mitotic activity (Grading criteria between II and III are highly variable among studies) Molecular/cytogenetic (based on location and age)

Postoperative

• C11orf95-RELA fusion (IHC)* • YAP1 fusion • H3K27M3 loss of nuclear expression (IHC)*

Integrated WHO diagnosis and international molecular subgroup consensus classification

Subependymoma

EPN

MPE

I

II-III

I

Intracranial (intraventricular, mostly 4th or lateral ventricles) Spinal (intramedullary, mostly cervical or cervicothoracic)

STR

PF

• C11orf95-RELA • YAP1

• H3K27M3 (A)

Subependymoma, I

ST-EPN-RELA ST-EPN-YAP1

PF-EPN-A PF-EPN-B

II

III

SP†

Spinal (conus medullaris, cauda equina, filum terminale)

SP-EPN

SP-MPE

GTR

STR

Radiotherapy (60 Gy)

Observation

Radiotherapy (>50 Gy)

Fair prognosis (EPN-B)

Fair prognosis

Fair prognosis

Upfront management (NCCN 2017 & EANO 2017) • Staging 2–3 weeks post-op. If staging positive: craniospinal irradiation (36 Gy) + focal boost

Observation (some would argue for radiotherapy if STR)

GTR

STR

Observation or radiotherapy

Radiotherapy (54–59·5 Gy)

Surveillance MRI Every 3–4 months x 1 year, then Every 4–6 months x 1 year, then Every 6–12 months lifelong Best prognosis Prognosis (in adult patients)

Poor prognosis (RELA) (EPN-A)

Figure 2: Simplified diagnostic decision-tree for adults’ ependymal tumours IHC=immunohistochemistry. RELA=reticuloendotheliosis viral oncogene homologue A. NCCN=National Comprehensive Cancer Network. EANO=European Association of Neuro-Oncology. EPN=ependymoma. STR=supratentorial. PF=posterior fossa. MPE=myxopapillary ependymoma. GTR=gross total resection. STR=subtotal resection. *Different immunohistochemistry surrogates can be used for the C11orf95-RELA fusion and the H3 Lys27Met3 loss of nuclear expression, defining ST-EPN-RELA and PF-EPN-A, respectively. At our institution, we use L1CAM for the RELA fusion. PF-EPN-A was originally defined by methylome or expression profiling; our institution similarly uses an H3Lys27Met3 (ie, trimethylated lysine 27 of histone 3) surrogate. In patients with neurofibromatosis type 1, spinal ependymoma are mostly found in the cervical region. †In spinal ependymoma, NF1 inactivation is common, although not used for integrated diagnosis.

6

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

Seminar

maximal safe resection improves functional status and reduces mortality in both low-grade65 and high-grade gliomas.6,66,67 The extent of resection is largely dependent on tumour location, surgeon experience, and use of pre-operative and intra-operative techniques.68–70 In tumours adjacent to eloquent brain regions, extensive safe resection can be achieved with pre-operative imaging techniques localising functional cortical areas and their subcortical pathways via functional MRI62,71 and diffusion tensor imaging,62,72 respectively, although awake surgery with intraoperative cortical electrode mapping remains the gold standard.73 Generally, a contrast MRI should be done within 72 h post-surgery to determine the extent of resection.6

Upfront management by tumour type In this Seminar, a treatment overview is provided for most frequent adult primary brain tumours (figures 1 and 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.

Pilocytic astrocytoma (WHO I) Pilocytic astrocytomas are the most common noninfiltrative low-grade gliomas (panel). They tend to arise mainly in the cerebellum, spinal cord, and optic path­ way, the latter being especially frequent among neuro­ fibromatosis type 1 patients. Pilocytic astrocytomas appear to represent a so-called single pathway disease, with only alterations in the RAS-RAF-MEK-ERK cellular signalling pathway identified to date.31 Prognosis is generally excellent (table 1), although survival signifi­ cantly declines with increasing age and decreasing extent of resection.1,11 Gross total resection is the standard of care, and carries the most favourable prognosis, with reported 10 years overall survival as high as 100%, as compared with 74% for those subtotally resected.11,75 Even in cases of subtotal resection, postoperative surveillance is recommended.76,77 The role of upfront adjuvant chemo­ therapy or radiotherapy for subtotally resected pilocytic astrocytoma is a subject of debate.77–80

Diffuse low grade gliomas (WHO II) Diffuse low-grade gliomas include WHO grade II diffuse astrocytomas and oligodendrogliomas (panel). Early and maximal safe resection is the initial treatment for those patients.6,7,81 Postoperative treatment decisions are based on risk stratification, although the delineation between low-risk and high-risk low-grade glioma is highly variable in the scientific literature.82 The 2016 WHO update classifies low-grade gliomas into three diagnostic and prognostic subgroups based on

Malignant (32%)

Non-malignant (68%)

Other malignant tumours (8%)† Ependymal tumours (WHO II–III) Oligodendrogliomas (<2%)

(WHO II–III) (~1·5%) Diffuse astrocytomas (WHO II–III) (~5·5%)

Glioblastomas (WHO IV) (15%)

Other non-malignant tumours (7%)*

Meningiomas (WHO I–II) (37%)

Pituitary tumours (WHO I–II) (16%)

Nerve sheath tumours (WHO I) (8%)

Figure 3: Simplified representation of yearly incidence of primary brain tumours among adults from CBTRUS 2010–20141 *Other non-malignant tumours including choroid plexus papillomas, non-malignant neuronal and mixed neuronal-glial tumours, tumours of the sellar region, non-malignant tumours of the pineal region, non-malignant mesenchymal tumours, germ cell tumours, WHO grade I gliomas, and WHO grade I ependymal tumours, among others. †Other malignant tumours including anaplastic meningiomas, embryonal tumours, lymphomas, choroid plexus carcinomas, anaplastic gangliogliomas, pineoblastomas, and malignant peripheral nerve sheath tumours, among others.

IDH1/2 mutation and 1p/19q codeletion status.11,13 IDHmutant and 1p/19q codeleted tumours (which correspond to oligodendrogliomas) hold the best prog­nosis, followed by IDH-mutant and 1p/19q intact tumours, and by IDHwildtype tumours (figure 1). Patients with low-risk low-grade glioma are usually younger (≤40 years), neurologically intact, and are postgross total resection of an IDH-mutant +/– 1p/19q codeleted tumour.6,7,13 In these patients, a watch-andwait policy with MRI every 3–6 months is accepted6,7 based on the European Organisation for Research and Treatment of Cancer (EORTC) 22845 long-term analysis. This study showed equivalent survival with immediate radio­therapy versus deferred radiotherapy on pro­gress­ ion, although immediate radiotherapy signifi­cantly in­ creases progression-free survival by 2 years (appendix).83 No prospective data are currently available regard­ ing observation versus immediate chemoradiation for those patients. Patients with high-risk low-grade glioma are clinically defined as older than 40 years, have neurological symptoms, large tumour (>5 cm), or subtotal resection. These parameters are based on risk stratification in the phase 3 trials EORTC 22033-2603384 and RTOG 9802.8,85 IDH-wildtype low-grade gliomas are now also considered high-risk, as they commonly share molecular features with IDH-wildtype glioblastoma and follow a similar

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

7

Seminar

Median age 5 year at diagnosis survival rate* (years)

10 year survival rate*

Major favourable prognostic biomarkers

Major negative prognostic biomarkers

Pilocytic astrocytoma (WHO I)

12

94%

>90%

BRAF-KIAA1549 fusion35,38

..

Oligodendroglioma (WHO II)

43

81%

65%

IDH1/2-mutation 1p/19q codeletion

..

Diffuse astrocytoma (WHO II)

48

50%

40%

IDH1/2-mutation

..

Anaplastic oligodendroglioma (WHO III)

50

57%

43%

IDH1/2-mutation 1p/19q codeletion

..

Anaplastic astrocytoma (WHO III)

53

30%

20%

.. IDH1/2-mutation MGMT methylation

Glioblastoma (WHO IV)

64

Ependymoma74 (WHO I-III)

45

5·5% 83%

NA

H3 K27M-mutation IDH1/2-mutation MGMT methylation

Close to 80%

..

RELA-fusion positive Gain of chromosome arm 1q

*Based on the 2007 pre-molecular era WHO classification. Molecular genetic alterations have recently been recognised as more powerful prognostic and predictive markers than histological appearance alone.6,44,45 For example, the current WHO grading poorly distinguished prognoses for grades II and III IDH-mutant astrocytomas. In the 2016 WHO Classification, grades II and III gliomas are further stratified into 3 diagnostic and prognostic subgroups based on their IDH, ATRX and 1p/19q status (figure 1).14,15 Among diffuse gliomas, the most important positive prognostic factors include IDH1/2 mutation, 1p/19 codeletion, and MGMT methylation.6

Table 1: Median age at diagnosis, average 5 and 10 year survival rate, and major prognostic biomarkers of selected primary brain tumours in adults

clinical course.2,11 IDH-wildtype astrocytomas are thus often treated like glioblastomas,2 although no trials have specifically evaluated this subgroup. In IDH-mutant high-risk low-grade gliomas, current post-surgical standard of care is focal radiotherapy to 50-54Gy86,87 followed by 6 cycles of adjuvant procarbazine, lomustine and vincristine (PCV),6 based on the recently published long-term data of the phase 3 trial RTOG 9802 (appendix).8 This trial compared standard radiotherapy to standard radiotherapy followed by six cycles of adjuvant PCV in high-risk low-grade glioma (defined as patients <40 years with subtotal resection or patients >40 years), and demonstrated increase in progressionfree survival and overall survival after treatment with combined treatment: median progression-free survival increased from 4·0 to 10·4 years and median overall survival went from 7·8 to 13·3 years (hazard ratio [HR] 0·59; p=0·003).8 Findings of this trial also showed that initial treatment with radiation plus PCV is superior to initial radiation followed by PCV at progression. However, in current practice, PCV is often replaced by lomustine alone due to fewer toxic effects and the notion that vincristine does not pass the blood-brain barrier and that procarbazine has very limited efficacy. Moreover, temozolomide, a more tolerable alkylating agent, is often used in place of PCV.7 Over time, the recognition that anaplastic oligo­ dendrogliomas are chemosensitive,6,9,10,24 coupled with the hope of deferring cognitive risks of radiation, created interest in exploring upfront chemotherapy alone in highrisk low-grade glioma, particularly oligodendro­ gliomas. 8

Whereas chemotherapy alone has not yet been formally compared to chemoradiation in low-grade glioma, the first results from the phase 3 trial EORTC 22033-26033 comparing dose-dense temozolomide alone to radiotherapy alone in high-risk low-grade glioma (defined as one of: >40 years of age, progressive disease, tumour >5 cm or crossing midline, or neurological symptoms) were recently published.84 Surprisingly, there was no difference in progression-free survival among treatment groups, and especially among 1p/19 co-deleted low-grade glioma.84 However, long-term analysis is needed to establish the effect on overall survival.

Diffuse high grade gliomas (WHO III) Diffuse high-grade gliomas include WHO grade III anaplastic astrocytomas and anaplastic oligodendro­ gliomas (panel). The standard of care for patients with high-grade gliomas is maximal safe surgical resection followed by chemoradiation, based on the long-term results of three phase 3 trials,9,10,24 and on the first results of the CATNON trial88 (appendix). Chemoradiation consists of radiotherapy to 60 Gy with either six cycles of adjuvant PCV, or concurrent and adjuvant temozo­ lomide. The CATNON trial interim analysis published in 201788 showed that anaplastic astro­cytomas with intact 1p/19q status (eg, to exclude oligodendrogliomas) benefit from the addition of 12 cycles of temozolomide to radiotherapy as compared to radiotherapy alone (progression-free survival [PFS] 3·6 vs 1·5 years; median overall survival [OS] not reached vs 3·4 years; HR 0·65, 95% CI 0·45–0·93). Whether temozolomide can replace PCV in anaplastic oligodendroglioma 1p/19q codeleted tumours is cur­ rently being investigated in the CODEL trial, which compares radiotherapy followed by PCV with radio­ therapy with concurrent and adjuvant temozolomide. Whether radiotherapy can be deferred to prevent radiotherapy-induced neurotoxicity in those 1p/19q codeleted chemo­sensitive tumours is currently being investigated in the POLCA trial, comparing upfront radiotherapy plus PCV versus upfront PCV plus deferred radiotherapy at progression (appendix).

Glioblastoma (WHO IV) Glioblastoma is the most lethal of the primary brain tumours in adults; most patients do not survive beyond a year, and about 5% survive beyond 5 years.1 Only two phase 3 trials have reported an improvement in this prognosis over radiotherapy alone.33,89 In patients with good performance status (Karnofsky performance status [KPS] ≥60), radiotherapy to 60 Gy over 6 weeks with concurrent daily temozolomide, followed by at least six cycles of adjuvant temozolomide (5 days over 21 dayscycle) has been the standard of care since 2005 (compared with radiotherapy alone: HR 0·63, 95% CI 0·52–0·75; p<0·001; appendix).33 Pursuing adjuvant temozolomide over six cycles does not seem to prolong overall survival,

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

Seminar

Gene

Inheritance*

CNS tumours*

Main other tumours

Neurofibromatosis type 148,49

NF1

50% AD; 50% de novo

15-20% optic pathway glioma; 4% low-grade glioma (brainstem glioma); 1% glioblastoma†

Pheochromocytoma; leukaemia; neurofibromas; malignant peripheral nerve sheath tumours; gastrointestinal stromal tumours; rhabdomyosarcoma; early-onset breast tumour

Neurofibromatosis type 249

NF2

50% AD; 50% de novo

50% intracranial meningioma; 20% spinal meningioma; 30% spinal ependymoma; glioma

Bilateral vestibular schwannomas; non vestibular schwannomas

Schwannomatosis

SMARCB1

AD

Meningioma

Non vestibular schwannomas

Li-Fraumeni

TP53

80% AD; 20% de novo

Wide range of brain tumours Bone and soft tissue sarcoma; breast carcinoma; leukemia; adrenocortical reported in 20-60%; carcinoma; colorectal glioblastoma; medulloblastoma; choroid plexus carcinoma

Von Hippel-Lindau

VHL

80% AD; 20% de novo

80% haemangioblastoma; (cerebellum/spinal cord/ retina)

Renal cell carcinoma; pheochromocytoma; pancreatic neuroendocrine tumour; endolymphatic sac tumour; retinal angioma

Turcot type 1 (brain tumour-polyposis syndrome 1, hereditary non-polyposis cancer syndrome [HNPCC], constitutional mismatch repair cancer syndrome or deficiency, Lynch syndrome)

MMR genes: MLH1, PMS2, MSH2, MSH6, EPCAM

3% glioblastoma; (hypermutated phenotype)

Colorectal carcinoma; endometrial adenocarcinoma; carcinoma of the stomach, ovaries, small bowel, biliary tract, urothelial, and/or pancreas

Turcot type 2 (brain tumour-polyposis syndrome 2, familial adenomatous polyposis [FAP], Gardner syndrome)

APC

85% AD; 15% de novo

Medulloblastoma (WNT-activated)

Colorectal carcinoma; gastric; duodenal; pancreatic; bile duct; hepatoblastoma; thyroid

Gorlin syndrome50 (nevoid basal cell carcinoma)

PTCH1; SUFU

75% AD; 25% de novo

5% medulloblastoma (SHH-activated); meningioma

Basal cell carcinoma; sarcoma

Tuberous sclerosis complex

TSC1; TSC2

85% AD; 25% AD

10% subependymal giant cell astrocytoma

Renal angiomyolipoma; cardiac rhabdomyoma

Melanoma-astrocytoma51 (familial atypical multiple mole melanoma [FAMMM])

CDKN2A; CDKN2B; P14/ARF

AD

Astrocytoma; pleomorphic xanthoastrocytoma; meningioma

Melanoma; pancreatic; nerve sheath tumours

Breast cancer (BRCA)51

BRCA-1; BRCA-2

Glioma

Breast; ovarian; prostatic; pancreatic

Cowden syndrome (multiple hamartoma syndrome)

PTEN

50% AD; 50% de novo

Dysplastic gangliocytoma of the cerebellum (LhermitteDuclos syndrome)

Breast cancer; thyroid; renal cell cancer; colon cancer

DICER1 syndrome (pleuropulmonary blastoma familial tumour and dysplasia syndrome)

DICER1

AD

Pineoblastoma; pituitary blastoma

Pleuropulmonary blastoma; embyronal rhabdomyosarcoma; Wilms tumour; intraocular medulloepithelioma

Multiple endocrine neoplasia type 1 (Wermer syndrome)

MEN1

AD

Pituitary adenoma; ependymoma

Parathyroid adenomas; pancreatic neuroendocrine tumours; bronchial, duodenal and thymic carcinoids; adrenocortical adenomas; gastric enterochromaffin-like adenomas

AD=autosomal dominant. TP53=tumour protein p53. NF1=neurofibromatosis type 1. NF2=neurofibromatosis type 2. MMR=mismatch repair. APC=adenomatous polyposis coli. PTCH1=patched 1 tumour suppressor. TSC=tuberous sclerosis complex. CDKN=cyclin-dependent kinase inhibitor. VHL=von Hippel-Lindau tumour suppressor. *Approximately. †Prevalence of high-grade gliomas is 10-50 times higher in NF1 than it is in the general population.49

Table 2: Main familial tumour syndromes associated with primary brain tumours146,47

and exposes patients to ongoing treatment-related toxic effects, although the validating data are from a retrospective analysis of four randomised trials.90 In 2015, the interim analysis of a phase 3 trial reported significant survival benefit from the addition of alternating electric field therapy to adjuvant temo­zolomide, with minimal additional toxicity.89 In this trial, 695 patients were randomly assigned (2:1) to receive tumour treating fields plus adjuvant temozolomide or temozolomide alone.89 In

December, 2017, the final analysis reported that the tumour treating fields device added nearly 5 months to the median overall survival, from 16·0 to 20·9 months (HR 0·63, 95% CI 0·53–0·76; p<0·001), and increased the 5-year survival rate by a factor of 2·5, from 5% to 13% (appendix).91 Importantly, all subgroups benefited from the tumour treating fields, irrespective of age, sex, KPS, MGMTp status, or extent of resection.91 This device is now approved in Europe, Israel, Japan, Australia, and the

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

9

Seminar

USA, and now portends level 1 evidence in the 2018 NCCN guideline.6 In glioblastoma patients aged older than 70 years deemed not to be suitable to receive the conven­tional tionated radio­ 6 week radiotherapy regimen, hypofrac­ therapy over a 3-week course with concurrent and adjuvant temozolomide was recently shown to be superior to hypofractionated radiotherapy alone (9·3 vs 7·6 months; HR for death 0·67, 95% CI 0·56–0·80; p<0·001) and allowed reduced treatment time without sacrifice in quality of life.37 Other options include hypofractionated radiotherapy alone,36,92 or temo­zolomide alone35,36 in patients with MGMTp methylated tumours (appendix).6

Ependymoma (WHO I-II-III) Ependymomas represent near 2% of CNS tumours and 7% of all gliomas.1 They most commonly affect children and young adults, and the level of evidence for therapeutic interventions is thus higher in the paediatric population. Surgery is the mainstay of treatment and gross total resection is the most important independent prognostic factor among all grades (WHO I–II–III).43 In the case of subtotal resection, reoperation should be considered whenever possible to achieve a gross total resection.6 At least 2–3 weeks after surgery, all ependymomas, regardless of grade should be staged with a craniospinal MRI, followed by CSF cytology (when safe) in case of negative MRI,6 due to risk of CSF dissemination and its treatment implications. Metastatic ependymomas should receive craniospinal irradiation to 36Gy with boost to focal lesions (figure 2).6 Grade I ependymomas are non-infiltrative and often curable by gross total resection alone, and they can be observed when completely resected. Postoperative radiotherapy is usually employed in adult patients with intracranial grade III ependymomas (irrespective of the extent of resection) and in subtotally resected intracranial grade II ependymomas. Radiotherapy also is generally used in subtotally resected spinal ependy­ momas, regardless of the grade (figure 2).6,43,74 The role of chemotherapy remains unproven despite extensive investigation.

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 abovementioned options are used alone or in combination, and clinical trial participation is encouraged. There is no consensus regarding the most appropriate salvage agent, and the EANO7,74 and NCCN6 guide­lines are referred to for additional details regarding each tumour type. Potentially 10

targetable mutations and molecular alterations might be used to guide trial participation or use of approved targeted therapies.6 Generally, maximal safe re-operation is the treatment of choice for all recurrent tumours when feasible. Reradiation,93 various chemotherapy regimens, clinical trials, or palliative or best supportive care are also considered. Commonly used systemic chemotherapies for pro­ gressive or recurrent diffuse gliomas (grade II-III-IV) include temozolomide rechallenge,94–97 nitrosoureas,98 PCV99–101 and platinum-based regimens.102 In recurrent lowgrade glioma previously treated with chemotherapy alone, chemoradiation is preferred. There is no clear role for bevacizumab (an anti­angiogenic monoclonal antibody) in recurrent enhancing low-grade glioma.103 In recurrent high-grade gliomas and glio­blastoma, additional treatment options include carmu­ stine wafers,104,105 irinotecan106 or etoposide107 chemo­ therapies, bevacizumab, and tumour treating fields. Bevacizumab received an accelerated US Food and Drug Administration (FDA) approval in 2009 based on the findings of two phase 2 studies showing decreased peritumoral oedema and corticosteroids use, and significant increase in progression-free survival, but no improvement of overall survival.108,109 In 2017, the phase 3 trial EORTC 26101110 showed an increase in progression-free survival from the addition of bevacizumab to lomustine over lomustine alone (PFS 4·2 vs 1·5 months; HR 0·49, 95% CI 0·39–0·61), but not in overall survival, and resulted in full FDA approval (appendix). In 2011, the FDA approved tumour treating fields based on the results of a randomised trial with similar survival than other chemotherapies, but with less myelotoxicity and improved quality of life.111

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

Seizures Seizures are experienced by about two-thirds of glioma patients and require long-term treatment with antiepileptic drugs. Monotherapy, use of newer anti­ epileptic drugs, and lowest possible antiepileptic drug dose to achieve seizure control are preferable to avoid side-effects and drug-drug interactions.6,113,114 Surgery, radiotherapy, and chemo­ therapy also contribute to seizure control.115,116 For patients who have not had a seizure, routine antiepileptic drug prophylaxis is not recommended, but can be considered for a brief period perioperatively.6,117

Corticosteroids Almost all malignant brain tumour patients receive corticosteroids at some point, most commonly for symptomatic peritumoral vasogenic edema.114 Although

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

Seminar

there are no standardised guidelines for steroid dose, duration and taper schedule, dexamethasone is often preferred due to its lack of mineralocorticoid activity and its long half-life (36–54 h).118 Usual dosing vary between 2–16 mg daily depending on symptoms severity, with similar bioavailability orally or intravenously.

Venous thromboembolism Gliomas confer the highest risk for tumour-associated venous thromboembolism of all cancers.112 Up to 20% of high-grade gliomas patients develop sympto­ matic venous thromboembolism during the perioper­ ative period, and up to 30% at 1 year.118 Generally, post­ operative venous thromboembolism prophylaxis with com­ pression stocking and low-molecular-weight heparin within 12–24 hours of surgery is recommended until ambulation, and does not confer increased risk of major bleeding.119 Prolonged venous thromboembolism prophyl­axis over the peri­operative period is, however, not advised due to increased intracranial haemorrhage (5% vs 1%).120 Treatment of venous thromboembolism with low-molecular-weight heparin is recommended for at least 3–6 months in low-grade glioma, and lifelong in high-grade gliomas.121

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 tech­ nologies, which bypass the blood-brain barrier. There also is consensus that combination therapies may be required to achieve broad and durable antitumour response. Cancer immunotherapy is the stimulation of a patient’s immune system to activate specific immune cells to attack cancer cells. Immunotherapy strategies currently studied in brain tumours include cancer vaccines,122–124 oncolytic virotherapeutics,125,126 monoclonal antibodies (checkpoint inhibitors)127 and adoptive T-cell therapies (CAR T-cell)124 (appendix).128,129 Ongoing phase 3 vaccine trials include tumour lysate and peptide dendritic cell vaccine (NCT0045968 and NCT02546102, respectively). Several clinical trials of checkpoint inhibitors in glioblastoma are ongoing,127 including phase 2 and 3 trials of nivo­ lumab in newly diagnosed glioblastoma, with enrolment based on MGMTp methylation status (NCT02667587 and NCT02617589). Targeted therapies inhibit aberrant signalling path­ ways in primary brain tumours. The majority of targeted agents are either extracellular monoclonal antibodies or intra­ cellular small molecule tyrosine kinase inhibitors.

Fre­quent signalling pathways targeted are tumour growth factor pathways (such as PDGF/PDGFR, EGF/EGFR), angiogenesis pathways (VEGF/VEGFR), and the intra­ cellular pathways downstream of both (such as PI3K/AKT/ mTOR pathway,130 MAPK pathway, and poly[ADP-ribose] polymerase [PARP] system). Other molecular targets include histone deacetylases and proteasomes. The only ongoing phase 3 targeted therapy trial in glioma evaluates the addition of PARP inhibitor veliparib in MGMTp methylated glioblastoma patients (NCT02152982). Gene therapy uses viruses, cellular carriers (stem cells), and nanomolecules as vectors to deliver genes into the target cells and modify known oncogenic mu­ tations or sensitise tumour cells to treatment.125 Ongoing trials in recurrent high-grade gliomas include the phase 2/3 Toca 5 trial using a replication-competent retro­virus vector (NCT02414165), and phase I trials using genetically modified neural stem cells (NCT02192359, NCT02015819). Convection-enhanced delivery delivers larger molecules directly to the CNS via stereotactically placed catheters, bypassing systemic toxicity. By using a pressure gradient rather than a concentration gradient, more effective con­ centrations of agents can reach the tumour. Com­ pounds created to be delivered via convection-enhanced delivery include a recombinant fusion toxin composed of IL-13 and a modi­ fied form of the Pseudomonas exotoxin (NCT02858895), and nanoliposomal-irinotecan (NCT02022644). The Cancer Cell Map Initiative131 is a new effort focusing on mapping the cancer gene network to identify key tumour drivers and the genetic influences on treatment responses. Such mapping will lead to the development of biomarker-based trials where treatment is based on molecular drivers rather than histology alone.131–133 Such genomic platforms are likely to improve patient diagnosis, risk stratification, and treatment selection in the near future.134 Biomarker-driven trials for primary brain tumours patients include INSIGhT (NCT02977780), N2M2 (NCT03158389), and GBM AGILE.135

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 com­ bination therapy show promise and provide hope. In addition, further analysis of tumour DNA, RNA, and proteins might further refine what should be targeted (eg, proliferation and invasion pathways simul­taneously) and lead to enrichment strategies in early phase trials. Ideally, a collaborative effort among institutions will lead to a platform that contains clinical, pathologic, genomic, imaging, and epidemiology

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

11

Seminar

data from institutions globally, optimised to address the challenges of security, scalability, and collaboration.

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 neurooncology. 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 infusion of ex-vivo prepared immune cells are promising strategies. The present challenge is to translate this better understanding of the pathophysiology into effective therapies. Contributors SL did the systematic review, the writing of the paper, and participated to the conception of the figures. AP and NAB participated in the editing of the manuscript. Declaration of interests NAB has research funding from the following industry partners: BMS, Beigene, Celldex, Deciphera, Delmar, EpicentRx, Five Prime, Kadmon, Eli Lilly, Medicenna, Istari, Orbus, Tocagen, VBL, Arbor. He has performed CME talks on behalf of Genentech/Roche and served on the advisory boards of GW, Genentech/Roche, Medicenna, VBL. SL and AP declare no competing interests. Acknowledgments We thank Ilona Garner for her help with corrections and modifications of the paper, Evans Whitaker for his assistance with the literature search, and Kenneth X Probst for the figures design. References 1 Ostrom QT, Gittleman H, Liao P, et al. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol 2017; 19: 1–88. 2 Louis DN, Ohgaki H, Wiestler OD CW. (2016) WHO classification of Tumours of the central nervous system (revised 4th edition). World Health Organization: Lyon, 2016. 3 Rossetti AO, Stupp R. Epilepsy in brain tumor patients. Curr Opin Neurol 2010; 23: 603–9. 4 Giulioni M, Marucci G, Martinoni M, et al. Epilepsy associated tumors: review article. World J Clin Cases 2014; 2: 623–41. 5 Kirby S, Purdy RA. Headaches and brain tumors. Neurol Clin NA 2014; 32: 423–32. 6 National Comprehensive Cancer Network. Central nervous system cancers (version 1.2018). https://www.nccn.org/professionals/ physician_gls/pdf/cns.pdf (accessed Nov 22, 2017). 7 Weller M, van den Bent M, Tonn JC, et al. European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Rev Lancet Oncol 2017; 18: 315–29. 8 Buckner JC, Shaw EG, Pugh SL, et al. Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma. N Engl J Med 2016. DOI:10.1056/NEJMoa1500925. 9 Cairncross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol 2012; 31: 1–10. 10 Van Den Bent MJ, Brandes AA, Taphoorn MJB, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of extent of resectionTC Brain Tumor Group Study 26951. J Clin Oncol 2013; 31: 344–50. 11 Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous System: a summary. Acta Neuropathol 2016; 131: 803–20.

12

12 Karremann M, Gielen GH, Hoffmann M, et al. Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neuro Oncol 2018; 20: 123–31. 13 Buckner J, Giannini C, Eckel-Passow J, et al. Management of diffuse low-grade gliomas in adults: use of molecular diagnostics. Nat Publ Gr 2017; 13: 340–51. 14 Eckel-Passow JE, Lachance DH, Molinaro AM, et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 2015; 372: 2499–508. 15 Batista R, Cruvinel-Carloni A, Vinagre J, et al. The prognostic impact of TERT promoter mutations in glioblastomas is modified by the rs2853669 single nucleotide polymorphism. Int J Cancer 2016; 139: 414–23. 16 Labussière M, Di Stefano AL, Gleize V, et al. TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations. Br J Cancer 2014; 111: 2024–32. 17 Simon M, Hosen I, Gousias K, et al. TERT promoter mutations: a novel independent prognostic factor in primary glioblastomas. Neuro Oncol 2015; 17: 45–52. 18 Chan AK-Y, Yao Y, Zhang Z, et al. TERT promoter mutations contribute to subset prognostication of lower-grade gliomas. Mod Pathol 2015; 28: 177–86. 19 Gia Vuong H, Altibi AM, Duong UN, et al. TERT promoter mutation and its interaction with IDH mutations in glioma_ Combined TERT promoter and IDH mutations stratifies lower-grade glioma into distinct survival subgroups: a meta-analysis of aggregate data. Crit Rev Eukaryot Gene Expr 2018; 120: 1–9. 20 Wick W, Hartmann C, Engel C, et at. NOA-04 randomized phase III trial of tequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 2009; 27: 5874–80. 21 Wesseling P, Van Den Bent M, Perry A. Oligodendroglioma: pathology, molecular mechanisms and markers. Acta Neuropathol 2015; 129: 809–27. 22 Weller M, Stupp R, Hegi ME, et al. Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice. Neuro Oncol 2012; 14: 100–08. 23 Jenkins RB, Blair H, Ballman K V, et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res 2006; 66: 9852–61. 24 Wick W, Roth P, Hartmann C, et al. Long-term analysis of the NOA-04 randomized phase 3 trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol 2016; 18: 1529–37. 25 Wu G, Broniscer A, McEachron TA, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 2012; 44: 251–53. 26 Schwartzentruber J, Korshunov A, Liu X-Y, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012; 482: 226–32. 27 Khuong-Quang DA, Buczkowicz P, Rakopoulos P, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 2012; 124: 439–47. 28 Bender S, Tang Y, Lindroth AM, et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 2013; 24: 660–72. 29 Chan K, Fang D, Gan H, et al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev 2013; 27: 985–90. 30 Fontebasso AM, Liu X-Y, Sturm D, Jabado N. Chromatin remodeling defects in pediatric and young adult glioblastoma: a tale of a variant histone 3 tail. Brain Pathol 2012; 23: 210–16. 31 Ferris SP, Hofmann JW, Solomon DA, Perry A. Characterization of gliomas: from morphology to molecules. Virchows Arch 2017; 471: 257–69. 32 Castel D, Philippe C, Calmon R, et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol 2015; 130: 815–27.

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

Seminar

33 Stupp R, Mason WP, Van Den Bent MJ, et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med 2005; 352: 987–96. 34 Hegi ME, Diserens A-C, Gorlia T, et al. MGMT Gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352: 997–1003. 35 Wick W, Platten M, Meisner C, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 2012; 13: 707–15. 36 Malmström A, Grønberg BH, Marosi C, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol 2012; 13: 916–26. 37 Perry JR, Laperriere N, O’Callaghan CJ, et al. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med 2017; 376: 1027–37. 38 Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase 3 clinical trial. J Clin Oncol 2013; 31: 4085–91. 39 Zawlik I, Vaccarella S, Kita D, Mittelbronn M, Franceschi S, Ohgaki H. Promoter methylation and polymorphisms of the MGMT gene in glioblastomas: a population-based study. Neuroepidemiology 2009; 32: 21–29. 40 Hawkins C, Walker E, Mohamed N, et al. BRAF-KIAA1549 Fusion Predicts Better Clinical Outcome in Pediatric Low-Grade Astrocytoma. Clin Cancer Res Cancer Res 2011; 17: 4790–8. 41 Park S-H, Won J, Kim S-I, et al. Molecular testing of brain tumor. J Pathol Transl Med 2017; 51: 205–23. 42 Sturm D, Pfister SM, Jones DTWW, Stefan MP, Jones DTWW. Pediatric gliomas: current concepts on diagnosis, biology, and clinical management. J Clin Oncol 2017; 35: 2370–7. 43 Pajtler KW, Mack SC, Ramaswamy V, et al. The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 2017; 133: 5–12.
 44 Reuss DE, Mamatjan Y, Schrimpf D, et al. IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO. Acta Neuropathol 2015; 129: 867–73. 45 Hartmann C, Hentschel B, Wick W, et al. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol 2010; 120: 707–18. 46 Evans DG, Howard E, Giblin C, et al. Birth incidence and prevalence of tumor-prone syndromes: Estimates from a UK family genetic register service. Am J Med Genet Part A 2010; 152: 327–32. 47 Dunbar EM, Eppolito A, Henson JW. Genetic counseling and tumor predisposition in neuro-oncology practice. Neuro Oncol Practice 2016; 3: 17–28. 48 Anderson JL, Gutmann DH. Neurofibromatosis type 1. Handb Clin Neurol 2015; 132: 75–86. 49 Campian J, Gutmann DH. CNS tumors in neurofibromatosis. J Clin Oncol 2017; 35: 2378–85. 50 Barankin B, Goldenberg G. Nevoid basal cell carcinoma syndrome. UpToDate. In: Post T, ed. UpToDate. Waltham: UpToDate, 2017. 51 Kyritsis AP, Bondy ML, Rao JS, Sioka C. Inherited predisposition to glioma. Neuro Oncol 2010; 12: 104–13. 52 Braganza MZ, Kitahara CM, Berrington de González A, Inskip PD, Johnson KJ, Rajaraman P. Ionizing radiation and the risk of brain and central nervous system tumors: a systematic review. Neuro Oncol 2012; 14: 1316–24. 53 Lee EQ, Schiff D, Wen PY. Neurologic complications of cancer therapy. New York: Demos Medical, 2011. 54 Wrensch M, Minn Y, Chew T, Bondy M, Berger MS. Epidemiology of primary brain tumors: Current concepts and review of the literature. Neuro Oncol 2002; 4: 278–99. 55 Coble JB, Dosemeci M, Stewart PA, et al. Occupational exposure to magnetic fields and the risk of brain tumors. Neuro Oncol 2009; 11: 242–49. 56 Kheifets L, Ahlbom A, Crespi CM, et al. A pooled analysis of extremely low-frequency magnetic fields and childhood brain tumors. Am J Epidemiol 2010; 172: 752–61.

57 Carlberg M, Hardell L. Evaluation of Mobile Phone and Cordless Phone Use and Glioma Risk Using the Bradford Hill Viewpoints from 1965 on Association or Causation. Biomed Res Int 2017. DOI:10.1155/2017/9218486. 58 Wang Y, Guo X. Meta-analysis of association between mobile phone use and glioma risk. J Cancer Res Ther 2016; 12: C298–300. 59 Yang M, Guo W, Yang C, et al. Mobile phone use and glioma risk: A systematic review and meta-analysis. PLoS One 2017; 12: e0175136. 60 Baan R, Grosse Y, Lauby-Secretan A, et al. Carcinogenicity of radiofrequency electromagnetic fields. Lancet Oncol 2011; 12: 624–26. 61 Morgan LL, Miller AB, Sasco A, Davis DL. Mobile phone radiation causes brain tumors and should be classified as a probable human carcinogen (2A) (Review). Int J Oncol 2015; 46: 1865–71. 62 Brindle KM, Izquierdo-Garcia JL, Lewis DY, Mair RJ, Wright AJ. Brain Tumor Imaging. J Clin Oncol 2017; 35: 2432–39. 63 Mabray MC, Barajas RF, Cha S. Modern brain tumor imaging. Brain Tumor Res Treat 2015; 3: 8–23. 64 Bangiyev L, Camilla M, Espagnet R, et al. Adult brain tumor imaging: state of the art. Semin Roentgenol 2014; 49: 39–52. 65 van den Bent MJ, Smits M, Kros JM, et al. Diffuse infiltrating oligodendroglioma and astrocytoma. J Clin Oncol 2017; 35: 2394–401. 66 Noorbakhsh A, Tang JA, Marcus LP, et al. Gross-total resection outcomes in an elderly population with glioblastoma: a SEER-based analysis. J Neurosurg 2014; 120: 31–39. 67 Chaichana KL, Jusue-Torres I, Navarro-Ramirez R, et al. Establishing percent resection and residual volume thresholds affecting survival and recurrence for patients with newly diagnosed intracranial glioblastoma. Neuro Oncol 2014; 16: 113–22. 68 Aldave G, Tejada S, Pay E, et al. Prognostic value of residual fluorescent tissue in glioblastoma patients after gross total resection in 5-aminolevulinic acid-guided surgery. Neurosurgery 2013; 72: 915–21. 69 Ferraro N, Barbarite E, Albert TR, et al. The role of 5-aminolevulinic acid in brain tumor surgery: a systematic review. Neurosurg Rev 2016; 39: 545–55. 70 Rao G. Intraoperative MRI and maximizing extent of resection. Neurosurg Clin N Am 2017; 28: 477–85. 71 Berntsen EM, Gulati S, Solheim O, et al. Functional magnetic resonance imaging and diffusion tensor tractography incorporated into an intraoperative 3-dimensional ultrasound-based neuronavigation system: impact on therapeutic strategies, extent of resection, and clinical outcome. Neurosurgery 2010; 67: 251–64. 72 Abhinav K, Yeh F-C, Mansouri A, Zadeh G, Fernandez-Miranda JC. High-definition fiber tractography for the evaluation of perilesional white matter tracts in high-grade glioma surgery. DOI:10.1093/ neuonc/nov113. 73 Hervey-Jumper SL, Berger MS. Maximizing safe resection of low- and high-grade glioma. J Neurooncol 2016; 130: 269–82. 74 Rudà R, Reifenberger G, Frappaz D, et al. EANO guidelines for the diagnosis and treatment of ependymal tumors. Neuro Oncol 2018; 20: 445–56. 75 Forsyth PA, Shaw EG, Scheithauer BW, et al. Supratentorial pilocytic astrocytomas. A clinicopathologic, prognostic, and flow cytometric study of 51 patients. Cancer 1993; 72: 1335–42. 76 Bornhorst M, Frappaz D, Packer RJ. Pilocytic astrocytomas. 2016 DOI:10.1016/B978-0-12-802997-8.00020-7. 77 Brown PD, Buckner JC, O’Fallon JR, et al. Adult patients with supratentorial pilocytic astrocytomas: a prospective multicenter clinical trial. Int J Radiat Oncol Biol Phys 2004; 58: 1153–60. 78 Kidd EA, Mansur DB, Leonard JR, Michalski JM, Simpson JR, Perry A. The efficacy of radiation therapy in the management of grade I astrocytomas. J Neurooncol 2006; 76: 55–58. 79 Burkhard C, Di Patre P-L, Schüler D, et al. A population-based study of the incidence and survival rates in patients with pilocytic astrocytoma. J Neurosurg 2003; 98: 1170–74. 80 Johnson DR, Brown PD, Galanis E, Hammack JE. Pilocytic astrocytoma survival in adults: analysis of the surveillance, epidemiology, and end results program of the national cancer institute. J Neurooncol 2012; 108: 187–93.

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

13

Seminar

81 Jakola AS, Skjulsvik AJ, Myrmel KS, et al. Surgical resection versus watchful waiting in low-grade gliomas. Ann Oncol 2017; 28: 1942–48. 82 Gorlia T, Wu W, Wang M, et al. New validated prognostic models and prognostic calculators in patients with low-grade gliomas diagnosed by central pathology review: a pooled analysis of extent of resectionTC/RTOG/NCCTG phase 3 clinical trials. Neuro Oncol 2013; 15: 1568–79. 83 van den Bent M J, Afra D, de Witte O, M et al. FK. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the extent of resectionTC 22845 randomised trial. Lancet 2005; 366: 985–90. 84 Baumert BG, Hegi ME, van den Bent MJ, et al. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (extent of resectionTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 2016; 17: 1521–32. 85 Daniels TB, Brown PD, Felten SJ, et al. Validation of extent of resectionTC Prognostic Factors for Adults with Low- Grade Glioma: a Report Utilizing Intergroup 86-72-51 1. Int J Radiat Oncol Biol Phys 2011; 81: 218–24. 86 Karim ABMF, Maat B, Hiitlevoll R, et al. A randomized trial on doseresponse in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int I Radiat Oncol Bid Phys 1996; 36: 549–56. 87 Shaw E, Arusell R, Scheithauer B, et al. Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a north central cancer treatment group/radiation therapy oncology group/eastern cooperative oncology group study. J Clin Oncol 2002; 20: 2267–76. 88 van den Bent MJ, Baumert B, Erridge SC, et al. Interim results from the CATNON trial (extent of resectionTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet 2017; 390: 1645–53. 89 Stupp R, Taillibert S, Kanner AA, et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA 2015; 314: 2535–43. 90 Blumenthal DT, Gorlia T, Gilbert MR, et al. Is more better? The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma: a secondary analysis of extent of resectionTC and NRG Oncology/RTOG. Neuro Oncol 2017; 19: 1119–26. 91 Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma a randomized clinical trial. JAMA 2017; 318: 2306–16. 92 Roa W, Brasher PMA, Bauman G, et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 2004; 22: 1583–88. 93 Combs SE, Thilmann C, Edler L, Debus J, Schulz-Ertner D. Efficacy of fractionated stereotactic reirradiation in recurrent gliomas: long-term results in 172 patients treated in a single institution. J Clin Oncol; 23: 8863–69. 94 van den Bent MJ, Keime-Guibert F, Brandes AA, et al. Temozolomide chemotherapy in recurrent oligodendroglioma. Neurology 2001; 57: 340–42. 95 van den Bent MJ, Taphoorn MJB, Brandes AA, et al. Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. J Clin Oncol 2003; 21: 2525–28. 96 Perry JR, Be K, Mason WP, et al. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE Study. J Clin Oncol 2010; 28: 2051–58. 97 van den Bent MJ, Chinot O, Boogerd W, et al. Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: extent of resectionTC brain tumor group phase 2 study 26972. Ann Oncol Off J Eur Soc Med Oncol 2003; 14: 599–602. 98 Wick W, Puduvalli VK, Chamberlain MC, et al. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol 2010; 28: 1168–74. 99 Van Den Bent MJ, Erdem-Eraslan L, Idbaih A, et al. MGMT-STP27 methylation status as predictive marker for response to PCV in anaplastic oligodendrogliomas and pligoastrocytomas. A report from extent of resection TC study 26951. Clin Cancer Res 2013; 19: 5513–22. 14

100 Brandes AA, Tosoni A, Vastola F, et al. Efficacy and feasibility of standard procarbazine, lomustine, and vincristine chemotherapy in anaplastic oligodendroglioma and oligoastrocytoma recurrent radiotherapy: a phase 2 study. Cancer 2004; 101: 2079–85. 101 Triebels VHJM, Taphoorn MJB, Brandes AA, et al. Salvage PCV chemotherapy for temozolomide-resistant oligodendrogliomas. Neurology 2004; 63: 904–06. 102 Brandes AA, Basso U, Vastola F, et al. Carboplatin and teniposide as third-line chemotherapy in patients with recurrent oligodendroglioma or oligoastrocytoma: a phase 2 study. Ann Oncol Off J Eur Soc Med Oncol 2003; 14: 1727–31. 103 Van Den Bent MJ, Klein M, Smits M, et al. Final results of the extent of resectionTC Brain Tumor Group randomized phase 2 TAVAREC trial on temozolomide with or without bevacizumab in 1st recurrence grade II/III glioma without 1p/19q co-deletion. 2017. https://meetinglibrary.asco.org/record/153220/abstract (accessed Nov 7, 2017). 104 Valtonen S, Timonen U, Toivanen P, et al. Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 1997; 41: 44–49. 105 Westphal M, Hilt DC, Bortey E, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol 2003; 5: 79–88. 106 Chamberlain MC, Wei-Tsao DD, Blumenthal DT, Glantz MJ. Salvage chemotherapy with CPT-11 for recurrent temozolomide-refractory anaplastic astrocytoma. Cancer 2008; 112: 2038–45. 107 Fulton D, Urtasun R, Forsyth P. Phase II study of prolonged oral therapy with etoposide (VP16) for patients with recurrent malignant glioma. J Neurooncol 1996; 27: 149–55. 108 Friedman HS, Prados MD, Wen PY, et al. Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma. J Clin Oncol 2009; 27: 4733–40. 109 Kreisl TN, Kim L, Moore K, et al. Phase II Trial of Single-Agent Bevacizumab Followed by Bevacizumab Plus Irinotecan at Tumor Progression in Recurrent Glioblastoma. J Clin Oncol 2009; 27: 740–45. 110 Wick W, Gorlia T, Bendszus M, et al. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med 2017; 377: 1954–63. 111 Stupp R, Wong ET, Kanner AA, et al. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: A randomised phase 3 trial of a novel treatment modality. Eur J Cancer 2012; 48: 2192–202. 112 Pace A, Dirven L, F Koekkoek JA, et al. European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma. Rev Lancet Oncol 2017; 18: e330–40. 113 Bénit CP, Vecht CJ. Neuro-Oncology Practice Seizures and cancer: drug interactions of anticonvulsants with chemotherapeutic agents, tyrosine kinase inhibitors and glucocorticoids. Neuro-Oncology Pract 2016; 3: 245–60. 114 Mohile NA. Medical Complications of brain tumors. Continuum (Minneap Minn) 2017; 23: 1635–52. 115 Rudà R, Bello L, Duffau H, Soffietti R. Seizures in low-grade gliomas: natural history, pathogenesis, and outcome after treatments. Neuro Oncol 2012; 14: iv55–iv64. 116 Avila EK, Chamberlain M, Schiff D, et al. Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials. Neuro Oncol 2017; 19: 12–21. 117 Glantz MJ, Cole BF, Forsyth pilocytic astrocytoma, et al. Practice parameter: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors: Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000; 54: 1886–93. 118 Schiff D, Lee EQ, Nayak L, Norden AD, Reardon DA, Wen PY. Medical management of brain tumors and the sequelae of treatment. Neuro Oncol 2015; 17: 488–504. 119 Alshehri N, Cote DJ, Hulou MM, et al. Venous thromboembolism prophylaxis in brain tumor patients undergoing craniotomy: a meta-analysis. J Neurooncol 2016; 130: 561–70. 120 Perry JR, Julian JA, Laperriere NJ, et al. PRODIGE: A randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost 2010; 8: 1959–65.

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

Seminar

121 National Comprehensive Cancer Network. Cancer-associated venous thromboembolic disease (version 1.2017). https://www.nccn.org/ professionals/physician_gls/pdf/vte.pdf (accessed Nov 22, 2017). 122 Filley AC, Dey M. Dendritic cell based vaccination strategy: an evolving paradigm. J Neurooncol 2017; 133: 223–35. 123 Weller M, Roth P, Preusser M, et al. Vaccine-based immunotherapeutic approaches to gliomas and beyond. Nat Rev Neurol 2017; 13: 363–74. 124 Bagley SJ, Desai AS, Linette GP, June CH, O’Rourke DM. CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges. Neuro Oncol 2018; published online March 2. DOI:10.1093/neuonc/noy032. 125 Gardeck AM, Sheehan J, Low WC. Immune and viral therapies for malignant primary brain tumors. Expert Opin Biol Ther 2017; 17: 457–74. 126 Lang FF, Conrad C, Gomez-Manzano C, et al. Phase I study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. J Clin Oncol 2018; 36: 1–10. 127 Huang J, Liu F, Liu Z, et al. Immune checkpoint in glioblastoma: promising and challenging. Front Pharmacol 2017; 8: 1–10. 128 Sampson JH, Maus MV, June CH. Immunotherapy for brain tumors. J Clin Oncol 2017; 35: 2450–56.

129 Lin Y, Okada H. Cellular immunotherapy for malignant gliomas. Expert Opin Biol Ther 2016; 16: 1265–75. 130 Zhao H, Wang J, Shao W, et al. Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development. Mol Cancer 2017; 16: 100. 131 Krogan NJ, Lippman S, Agard DA, Ashworth A, Ideker T. The cancer cell map initiative: defining the hallmark networks of cancer. Mol Cell 2015; 58: 690–98. 132 Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med 2017; 377: 62–70. 133 Trippa L, Alexander BM. Bayesian baskets: a novel design for biomarker-based clinical trials. J Clin Oncol 2017; 35: 681–87. 134 Alexander BM, Galanis E, Yung WKA, et al. Brain Malignancy Steering Committee clinical trials planning workshop: report from the Targeted Therapies Working Group. Neuro Oncol 2015; 17: 180–88. 135 Alexander BM, Ba S, Berger MS, et al. Adaptive global innovative learning environment for glioblastoma: GBM AGILE. Clin Cancer Res 2018; 24: 737–43. © 2018 Elsevier Ltd. All rights reserved.

www.thelancet.com Published online July 27, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30990-5

15