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. Author manuscript; available in PMC: 2024 Sep 1.
Published in final edited form as: Pediatr Blood Cancer. 2023 Aug 3;70(Suppl 6):e30600. doi: 10.1002/pbc.30600

Children’s Oncology Group’s 2023 Blueprint for Research: Central Nervous System Tumors

Sarah E S Leary 1,*, Arzu Onar-Thomas 2, Jason Fangusaro 3, Nicholas G Gottardo 4, Kenneth Cohen 5, Amy Smith 6, Annie Huang 7, Daphne Haas-Kogan 8, Maryam Fouladi 9, COG Central Nervous System Committee
PMCID: PMC10569820  NIHMSID: NIHMS1930175  PMID: 37534382

Abstract

Tumors of the central nervous system (CNS) are a leading cause of morbidity and mortality in the pediatric population. Molecular characterization in the last decade has redefined CNS tumor diagnoses and risk stratification; confirmed the unique biology of pediatric tumors as distinct entities from tumors that occur in adulthood; and led to the first novel targeted therapies receiving FDA approval for children with CNS tumors. There remain significant challenges to overcome: children with unresectable low-grade glioma may require multiple prolonged courses of therapy affecting quality of life; children with high-grade glioma have a dismal long-term prognosis; children with medulloblastoma may suffer significant short- and long-term morbidity from multimodal cytotoxic therapy, and approaches to improve survival in ependymoma remain elusive. The Children’s Oncology Group (COG) is uniquely positioned to conduct the next generation of practice-changing clinical trials through rapid prospective molecular characterization and therapy evaluation in well-defined clinical and molecular groups.

Keywords: pediatric low-grade glioma, diffuse midline glioma, medulloblastoma, ependymoma, CNS germ cell tumor

INTRODUCTION

Since the publication of the Children’s Oncology Group (COG) Blueprint for Research in 2013,[1] molecular characterization of central nervous system (CNS) tumors has transformed clinical diagnostic practice. Two revisions of the World Health Organization (WHO) classification of tumors of the CNS, published in 2016[2] and most recently in 2021 (WHO-CNS5),[3] have standardized clinical molecular characterization for pediatric CNS tumors. For the first time, novel targeted therapies have been Food and Drug Administration (FDA) approved for pediatric CNS tumors based on molecularly-defined, rather than histologically-defined, diseases.[4–7] However, the WHO does not dictate precise testing methods, and the complex diagnostic testing requirements may exacerbate inequities in care.[3] Retrospective molecular analyses of cohorts from the last generation of COG clinical trials have generated unprecedented, rich resources of clinical and molecular data[8–10] that inform the design of current and future studies incorporating clinical and molecular risk stratification to evaluate therapy in well-defined molecular entities.

The current generation of therapeutic clinical trials has incorporated prospective, rapid screening to determine risk stratification based on clinical and molecular risk factors. Through Project:EveryChild (APEC14B1, NCT02402244), the COG CNS Committee has incorporated molecular characterization into prospective screening for medulloblastoma, high-grade glioma, and low-grade glioma. The launch of the Molecular Characterization Initiative (MCI) in 2022, a partnership between the National Cancer Institute (NCI) Childhood Cancer Data Initiative (CCDI) and COG, offers free and rapid return of clinical molecular results (whole exome sequencing, methylation array, and fusion panel) in children with newly-diagnosed CNS tumors.

The rapid screening process also includes a COG-wide effort for improved technical radiologic staging by magnetic resonance imaging (MRI) for CNS tumors prone to leptomeningeal dissemination.[11–13] Current and future clinical trials for children with CNS tumors are dependent on precise diagnosis and staging. Proton therapy, increasingly available for children who require radiation therapy (RT), aims to spare healthy tissue and decrease late effects.[14] These critical advances may improve risk stratification, treatment, and outcomes for children with CNS tumors independent of the development of new therapies.

STATE OF THE DISEASE AND RECENT FINDINGS

Pediatric Low-Grade Glioma (pLGG)

Molecular characterization.

The MAPK pathway is the main oncogenic driver of pLGG, most commonly BRAF-KIAA1549 fusion or a BRAFV600E mutation.[15, 16] WHO-CNS5 characterizes pLGG into 4 groups: 1) diffuse astrocytoma, MYB- or MYB1-altered, 2) angiocentric glioma, 3) polymorphous pediatric-type low-grade neuroepithelial tumor of the young, and 4) diffuse LGG, MAPK pathway-altered.[3]

Overview and incidence.

pLGG, the most common CNS tumor in children, represents 30–40% of all pediatric brain tumors.[17] Tumors may be localized or, less commonly, disseminated and occur anywhere in the CNS. Five-year overall survival (OS) and event-free survival (EFS) are approximately 90% and 50%, respectively, and many patients suffer significant morbidities [3, 4] [5]. pLGG is now considered a chronic childhood disease.

Historically, standard treatment after surgical intervention included a combination of carboplatin and vincristine (CV) or vinblastine monotherapy, with 5-year OS and EFS of 86–94% and 45–53%, respectively.[18–20] RT, though effective, is used in rare cases when risks of poor outcome outweigh risks of neuro-endocrine and vascular abnormalities, and secondary malignancy.[21]

Recent findings.

A Pediatric Brain Tumor Consortium (PBTC) phase 2 study of the MEK 1/2 inhibitor selumetinib in patients with recurrent/progressive pLGG stratified according to histology, tumor location, NF1 and BRAF status, reported response rates of 24–40% with 2-year progression-free survival (PFS) of 70–96%. Toxicity profile was favorable compared to standard chemotherapy.[22, 23] These data led directly to current COG phase 3 trials ACNS1831 (NCT04166409), ACNS1833 (NCT03871257), ACNS1931 (NCT04576117), evaluating selumetinib.

In 2023, the FDA approved dabrafenib plus trametinib (D+T) for patients with pLGG with a BRAFV600E mutation requiring systemic therapy, based on results of a trial (NCT02684058) comparing D+T to CV in children with BRAFV600E-mutant pLGG.[4] Response rates and median PFS were 47% and 20.1 months, respectively, for D+T compared to 11% and 7.4 months for CV.[24]

Pediatric High-Grade Glioma (pHGG)

Molecular characterization.

The WHO-CNS5 has redefined HGG, creating separate categorizations for pediatric-type tumors that have therapeutic implications. Pediatric-type diffuse HGG (pHGG) now include: 1) DMG H3 K27-altered occurring in pons (diffuse intrinsic pontine glioma) and in other midline CNS structures (e.g. spine and thalamus), collectively defined as diffuse midline glioma (DMG); 2) diffuse hemispheric glioma H3 G34-mutant; 3) diffuse pediatric-type HGG H3-wildtype and IDH-wildtype; and 4) infant-type hemispheric gliomas driven by receptor tyrosine kinase (RTK) alterations in ALK, ROS1, NTRK and MET for which targeted therapies are available.[25]

Overview and incidence.

HGGs represent 10–15% of all pediatric brain tumors.[26] Staging for pHGGs includes brain and spine MRI. CSF cytology evaluation should be reserved for those with suspected metastatic disease.[27] Risk stratification is based on pHGG subtype. Prognostic clinical factors include extent of tumor resection and absence of metastatic disease. Outcomes for children with DMG, diffuse hemispheric glioma, and diffuse pediatric-type HGG remain dismal with 2-year OS of 10%.[28, 29] By contrast, patients with infant-type hemispheric HGG have a more favorable prognosis with conventional therapies and those with RTK alterations may benefit from targeted therapies.

Recent findings.

ACNS0423 (NCT00100802) evaluated dual alkylator therapy with temozolomide (TMZ) and lomustine in children with HGG and demonstrated a modest improvement in survival compared to TMZ alone in ACNS0126.[30] Other recent COG studies failed to show benefit of novel agents in newly-diagnosed HGG. ACNS0822 (NCT01236560) randomized HGG patients to bevacizumab, TMZ, or the histone deacetylase inhibitor vorinostat during RT followed by maintenance therapy with bevacizumab and TMZ;[31] ACNS0927 (NCT01189266) evaluated vorinostat during and following RT in DIPG patients;[32] and ACNS1721 evaluated the PARP inhibitor veliparib during RT and as adjuvant therapy with TMZ in for pHGG without H3 K27M or BRAFV600E mutation.[33] An early example of the benefit of prospective molecular profiling to identify children with ultra-rare tumors was demonstrated in a recent pilot trial of checkpoint inhibitor therapy with nivolumab (NCT02992964) showing anti-tumor response and prolonged survival in children with HGG and mismatch-repair deficiency or tumor hypermutation.[34]

Medulloblastoma

Molecular characterization.

Medulloblastoma, the most common malignant brain tumor of childhood, is one of the most comprehensively characterized human tumors. Medulloblastoma is comprised of four main molecular groups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3, and Group 4, each with distinct clinical, molecular, and prognostic characteristics. These groups can be further subdivided into molecular subtypes of prognostic importance.

Overview and incidence.

Risk-stratification of medulloblastoma based on age, extent of tumor resection, and presence of metastatic disease has classified patients >3 years into average-risk (<1.5cm2 residual tumor and no metastatic disease), and high-risk (either residual or metastatic disease); Young children may also be stratified by histology with nodular-desmoplastic histology conferring superior prognosis compared to classic or anaplastic histology. Patients with average-risk medulloblastoma have a 5-year OS of 80–85% using 23.4 Gy craniospinal irradiation (CSI) with a posterior-fossa boost to 55.8 Gy and alkylator and platinum-based chemotherapy,[36] while those with high-risk medulloblastoma have approximately 70% 5-year OS with 36 Gy CSI and platinum-based chemotherapy.[37, 38]

Recent findings.

In ACNS0331 (NCT00085735), a phase 3 average-risk medulloblastoma study, reduced RT boost volume from whole posterior fossa to tumor bed did not impact survival or local relapse rates. However, reduced CSI of 18 Gy for molecularly unselected children aged 3–7 years resulted in inferior survival.[8] In ACNS0332 (NCT00392327), a phase 3 high-risk medulloblastoma study, carboplatin given concurrently with radiotherapy improved survival for Group 3 medulloblastoma, but not WNT, SHH, or Group 4 patients; concurrent isotretinoin during maintenance conferred no benefit.[9] ACNS1221 (NCT02017964), a phase 2 dose-reduction trial for children <4 years with low-risk, non-metastatic nodular desmoplastic medulloblastoma (a surrogate marker for SHH Group), assessed a modified HIT SKK 2000 regimen but omitted intraventricular methotrexate. The study was closed early due to an unacceptable relapse rate, and confirmed the existence of two distinct infant SHH subtypes: SHH-1 and SHH-2, with inferior prognosis for SHH-1.[39] ACNS0334 (NCT00336024), a randomized trial for children < 3 years with high-risk medulloblastoma demonstrated improved response and survival with methotrexate in an intensive chemotherapy backbone. This benefit was observed exclusively in Group 3, as the SHH group had excellent survival. No benefit was observed in non-medulloblastoma embryonal tumors.[40]

These studies confirmed retrospective observations regarding the prognostic significance of molecular groups and several molecular markers within groups that further refine risk-stratification. [41–43] Molecular markers associated with excellent prognosis include WNT Group and chromosome 11 loss within Group 4. Molecular markers associated with poor prognosis include TP53 mutation, GLI2 amplification and 14q loss in SHH; and MYC amplification and isochromosome 17q in Group 3.[8, 9] Data from COG and other international prospective trials[38, 44] have refined risk stratification, incorporating molecular factors with clinical criteria.

These studies also confirmed the critical importance of radiologic staging. Retrospective central radiology review demonstrated that incorrectly staged patients were under- or over-treated, resulting in inferior survival[8, 36] or excessive toxicity.[9] To improve and confirm accurate staging, COG medulloblastoma studies now conduct centralized, rapid pathology, molecular, and diagnostic imaging reviews combined requiring optimized MRI sequences.[12]

Ependymoma

Molecular characterization.

Recent discoveries have delineated distinct clinical and molecular subgroups of ependymoma with therapeutic and prognostic implications. Supratentorial, posterior fossa, and spinal ependymomas are now considered anatomically distinct biological entities with defined molecular groups.[45, 46] WHO-CNS5 molecularly-defined groups include PFA and PFB tumors in the posterior fossa;[47–49] ZFTA (formerly RELA) fusion-positive and YAP1 fusion-positive supratentorial tumors;[48, 50] and MYCN-amplified spinal ependymoma.[45] While fusions and amplifications may be identified by DNA or RNA sequencing, epigenetic evaluation such as methylation array or histone H3 K27-trimethylation status is useful in discriminating between posterior fossa ependymoma entities.[47]

Overview and incidence.

Ependymoma accounts for approximately 10% of all pediatric brain tumors with 90% occurring intracranially [26]. Spinal cord ependymoma occurs in the contexts of Neurofibromatosis, type 2 or myxopapillary ependymoma. While increasing complete surgical resection and safe delivery of conformational radiation to young children have improved outcomes, 5-year EFS and OS remain 60–70% and 80–87%, respectively, and late relapses are common.[10, 51]

Recent findings.

ACNS0121 (NCT01407744), a phase 2 trial in newly-diagnosed ependymoma patients, established surgical resection followed by focal radiation as standard-of-care, suggesting that children with grade 2 supratentorial tumors could be observed safely following complete resection.[10] ACNS0831 (NCT01096368), the largest randomized phase 3 trial conducted for ependymoma, evaluated whether addition of maintenance chemotherapy would improve survival for patients following gross total resection and RT. While the trial suffered from significant patient non-compliance, there was no observed benefit to maintenance chemotherapy.[52] This trial confirmed clinicopathologic and molecularly-defined risk groups that serve as a platform for future trials and generated valuable data regarding patterns of failure, quality-of-life and long-term neurocognitive outcomes. Histologic grade remains relevant even in the context of molecular characterization, particularly when identifying patients with completely-resected, supratentorial tumors who can be safely observed. The study also highlighted the importance of molecular characterization and expert pathological review particularly for supratentorial ependymoma that can be confused with embryonal tumors, atypical teratoid rhabdoid tumor (ATRT), or other glioneuronal tumors.[53]

Atypical Teratoid Rhabdoid Tumors (ATRT)

Molecular characterization.

Genetic defects of core SWI/SNF complex subunits, encoded by SMARCB1 or rarely SMARCA4, leading to aberrant downstream epigenetic and signaling events represent the major oncogenic driver in ATRT which consists of three molecular sub-groups: SHH, TYR and MYC.[54, 55]

Overview and incidence.

ATRTs represent approximately 20% of CNS malignancies in children <3 years and the most common malignant brain tumor in children <1 year. Median age at diagnosis is 18–22 months; ~30% present with metastases.[56] Staging requires renal imaging as 35% may have Rhabdoid Tumor Predisposition Syndrome (RTPS). With contemporary multi-modality therapy, ATRT patients have 2–4 year OS of 32–53%. Prognostic factors include age, RPTS, tumor location, metastases, extent of surgery, intensive chemotherapy, and radiotherapy.[57–62]

Recent findings.

In ACNS0333 (NCT00653068), the first cooperative group ATRT-specific trial, high-dose chemotherapy and RT tailored to age, tumor location and stage, produced superior four-year EFS and OS of 37% and 42%, respectively, versus <10% in historical trials. Timing of RT did not affect survival and 91% of relapses occurred by two years from enrollment.[63] Tazemetostat, an EZH2 inhibitor, FDA approved for INI1-deficient epithelioid sarcoma, [64] has shown promising single-agent efficacy in recurrent ATRT in an early phase trial (NCT02601937).[65]

CNS Germ Cell Tumors (CNS-GCT)

Overview and incidence.

CNS-GCT, commonly pineal or suprasellar, represent 2–3% of pediatric CNS tumors in Western countries,[66–68] and can sometimes be diagnosed by assessing circulating tumor markers (alpha-fetoprotein and beta-human chorionic gonadotropin) in the blood and CSF. The exact cut-off values for tumor markers remain controversial and vary among US, European and Asian countries.[68] Sixty percent of CNS-GCT are pure germinomas and 40% are non-germinomatous germ-cell tumor (NGGCT).[66]. Germinomas are more responsive to therapy and have better survival outcomes compared to NGGCT.[69] Clinical staging requires brain and spine MRI, lumbar CSF cytology, and serum and CSF tumor markers.

Standard treatment for CNS GCT includes chemotherapy followed by RT. Although germinoma can be treated with CSI alone, multimodal treatment has been adopted internationally to minimize RT-associated late effects while maintaining excellent survival.[66] Specific chemotherapy agents and the volume/doses of RT vary among the US, European, and Asian countries.

Recent findings.

ACNS1123 (NCT01602666) evaluated RT dose and volume reduction in CNS-GCT. Germinoma patients with a complete response (CR) to four cycles of carboplatin and etoposide received 18 Gy whole ventricular RT (WVI) plus an additional 12 Gy boost to the tumor bed, whereas those with a partial response (PR) received 24 Gy WVI plus 12 Gy boost. Three-year PFS was 94.5% and 93.8% for the 18 Gy and 24 Gy WVI cohorts, respectively. However, the study failed to meet its success threshold for the 18 Gy regimen, partially due to patients lost to follow-up.[70]

For NGGCT patients receiving reduced dose and volume RT, three-year PFS/OS were 87.8 +/− 4.04% and 92.4 +/− 3.3% compared with 92% and 94.1% in the historical control who received CSI.[69, 71] Ten evaluable subjects experienced distant recurrence, which met the threshold for early closure; however, retrospective central review confirmed that only 8 patients eligible for reduced RT progressed. The study concluded that while patients with localized NGGCT with a CR/PR to induction chemotherapy had encouraging PFS when treated with reduced dose/volume RT, the spinal pattern of failure was concerning.[71, 72]

STRATEGIC APPROACH TO THERAPY AND KEY TRIALS TO BE PURSUED

Pediatric Low-grade Glioma (pLGG)

Strategy.

COG is conducting potentially practice-changing phase 3 clinical trials for pLGG for newly-diagnosed and previously-treated pLGG comparing standard chemotherapy to MEK- inhibitor (selumetinib)-containing regimens and evaluating critical functional and patient-reported outcomes.

Open and accruing trials

ACNS1831 (NCT03871257), a randomized phase 3 trial for children with neurofibromatosis, type 1 (NF1) and previously-untreated pLGG compares EFS with selumetinib to standard chemotherapy (CV). In optic pathway glioma patients, visual acuity is a co-primary end point.

ACNS1833 (NCT04166409), a randomized phase 3 trial for children with previously untreated non-NF1 and non-BRAFV600E mutant pLGG, also compares EFS with selumetinib to CV. Secondary objectives for both studies include assessment of motor, neurocognitive and patient-reported outcomes.

ACNS1931 (NCT04576117) a phase 3 trial evaluates the efficacy of vinblastine + selumetinib compared to selumetinib monotherapy in recurrent/progressive pLGG.

Both ACNS1833 and ACNS1931 require prospective histologic and molecular tumor profiling for eligibility screening and prognostic evaluation of specific molecular drivers

Priorities for trial development.

A priority for COG is to coordinate trans-Atlantic collaborative trials in rare tumor subgroups such as NF-1-associated LGG. ACNS1831, co-developed with European colleagues, is creating a framework for international collaboration and data sharing.

Pediatric High-Grade Glioma

Strategy.

The current strategy for pHGG is to leverage the growing understanding of the molecular underpinnings of specific tumor subtypes to efficiently evaluate the efficacy of novel agents in phase 2 studies in well-defined molecular cohorts. COG HGG clinical trials rely on rapid, free molecular testing through the MCI or study-specific targeted testing.

Open and accruing trials.

ACNS1723 (NCT03919071) for newly-diagnosed HGG with BRAFV600E mutation assesses the efficacy of dabrafenib and trametinib (combined BRAF and MEK inhibition) as maintenance therapy following focal radiation.

ACNS1821 (NCT05099003) for pediatric-type diffuse HGG H3-wildtype and IDH-wildtype and DMG H3 K27-altered tumors assesses the efficacy of the XPO1 inhibitor, selinexor. Infant-type hemispheric gliomas harboring RTK-mutations are eligible for targeted therapy trials in the recurrent setting via Pediatric MATCH.

Priorities for trial development.

A major priority is to develop more innovative and effective therapies for DMG H3K27-altered DIPGs and thalamic HGG which remain incurable.

Medulloblastoma

Strategy.

The dissection of the medulloblastoma genome has not yet yielded novel targeted therapies for most patients. The use of SMO inhibitors for children with SHH-driven medulloblastoma remains limited due to concerns for developmental toxicity.[73, 74] However, the implementation of an integrative risk-stratification system based on clinical, histological, and molecular criteria will allow more subgroup-specific therapy.[75] The focus of current COG front-line trials is to reduce treatment toxicity for low- and average-risk patients. COG medulloblastoma studies now incorporate centralized rapid prospective pathology, molecular and diagnostic imaging screening to confirm optimal staging and risk stratification.

Open and accruing trials.

ACNS1422 (NCT02724579) is a phase 2 trial for WNT medulloblastoma patients of reduced radiotherapy and chemotherapy. Following central review to verify strict low-risk eligibility criteria, patients receive 18 Gy CSI with a limited target volume boost to the tumor bed (to a total of 54 Gy) and a cumulative reduction of vincristine, cisplatin and lomustine of 40%, 33% and 33% respectively.

ACNS2031 (NCT05382338) is a phase 3 study based on the ACNS0331 backbone for children > 4 years assessing the ability of sodium thiosulfate (STS) to reduce cisplatin-associated hearing loss while maintaining survival in children with newly-diagnosed, average-risk medulloblastoma. This study is also evaluating radiation reduction to 18 Gy CSI for patients with clinically- and molecularly-defined, low-risk medulloblastoma, Group 4 with chromosome 11 loss.

Priorities for trial development.

Trials are under development for high-risk medulloblastoma and young children with medulloblastoma which will also adopt an integrative stratification system and incorporate subgroup specific therapy. The priority for high-risk patients will be to evaluate novel non-cytotoxic therapy in combination with backbone chemotherapy for both older and young children based on the feasibility of this strategy in the recently completed PBTC026 (NCT00867178) trial which incorporated vorinostat into an intensive chemotherapy backbone.[76] For young children with low-risk SHH group tumors, COG plans to evaluate an intensive chemotherapy regimen without methotrexate or radiation with careful attention to short and long-term neurocognitive outcomes in all patients.

Ependymoma

Strategy.

Critical to the design of upcoming studies is optimal patient stratification at diagnosis based on anatomic location, histopathologic diagnosis, grade, molecular characterization and meticulous central radiologic review for staging and extent of resection.

Priorities for trial development.

The next generation of ependymoma trials will incorporate multimodal risk stratification to identify groups of patients with high-risk disease (i.e., PFA tumors with 1q gain and/or 6q loss) for whom novel therapeutic approaches should be considered; and low-risk disease (i.e., PFB tumors, or supratentorial grade 2 tumors) for whom post-surgical observation or radiation avoidance strategies may be appropriate. Smaller phase 2 studies may be warranted to evaluate these specific strategies in rare clinically and molecularly defined cohorts.

Atypical Teratoid Rhabdoid Tumors (ATRT)

Strategy.

The strategy for ATRT is to evaluate novel non-cytotoxic agents given concurrently with an intensive chemoradiotherapy backbone in newly-diagnosed patients to address early relapses and reduce RT toxicity.

Priorities for trial development.

The next ATRT study will evaluate the feasibility and efficacy of tazemetostat incorporated in the ACNS0334 backbone and as maintenance therapy following response-based RT. CSF will be collected to develop response biomarkers for future trials.

CNS Germ Cell Tumors (GCT)

Strategy.

The strategy for CNS GCT is to reduce long-term, detrimental effects of RT while maintaining excellent survival.

Open and accruing trials.

ACNS2021 (NCT04684368), a phase 2 trial for NGGCT patients, utilizes the ACNS1123 chemotherapy backbone of ACNS1123 with whole ventricular and spinal canal RT to reduce spinal relapses. It is also evaluating the role of second-look surgery for patients with <PR after induction chemotherapy: those with persistent disease or elevated tumor markers will receive high-dose chemotherapy and autologous stem cell prior to RT.

Priorities for trial development.

An upcoming CNS germinoma study will evaluate further RT reduction in responders to induction chemotherapy. Key trial components will include prospective imaging review, evaluation of novel biomarkers, neurocognitive and QOL outcomes. Technologies including cell-free DNA may assist in diagnosis, classification, and prognostication.

Addressing Health Inequities and Disparities

An overarching priority for the COG CNS Committee is to understand and assess the impact of health inequities and disparities in children with CNS tumors. Among pediatric cancer patients, poverty and household material hardship are associated with decreased survival,[77,78] poorer quality of life, psychosocial, and emotional outcomes.[79–81] Specifically, lower income is associated with worse neurocognitive outcomes in medulloblastoma survivors.[82] Thus, socioeconomic-related demographics and household material hardship information will be collected current and upcoming studies as potential predictors of neurocognitive, quality-of-life, and psychosocial outcomes.

Conclusion

Although pediatric CNS tumors remain a leading cause of childhood morbidity and mortality, major advances in our understanding of tumor molecular underpinnings, many led by COG studies, offer great promise. COG is uniquely positioned to conduct the next generation of practice-changing clinical trials through ongoing collaborations with other consortia (e.g. PBTC and SIOPE) and rapid prospective molecular characterization in rarer, but well-defined clinical and molecular groups.

Funding support:

Grant support from the National Institute of Health, U10CA180886, U10CA180899, U10CA098543, U10CA098413, U24CA196173, U24CA114766.

Abbreviation Key:

ALK

Anaplastic lymphoma kinase

ATRT

atypical teratoid rhabdoid tumor

BRAF

v-raf murine sarcoma viral oncogene homolog B1

CCDI

Childhood Cancer Data Initiative

CNS

central nervous system

COG

Children’s Oncology Group

CR

complete response

CSI

craniospinal irradiation

CV

carboplatin, vincristine

D+T

dabrafenib plus trametinib

DIPG

diffuse intrinsic pontine glioma

DMG

diffuse midline glioma

DNA

Deoxyribonucleic acid

EFS

Event-free survival

EZH2

Enhancer of zeste homolog 2

FDA

Food and Drug Administration

GCT

Germ-cell tumor

Gli-2

Glioma-Associated Oncogene Family Zinc Finger 2

FDA

Food and Drug Administration

H3

histone 3

HGG

high-grade glioma

HIT-SKK

German Brain tumor protocol

IDH

Isocitrate dehydrogenase

INI-1

integrase interactor 1

LGG

Low-grade glioma

MAPK

mitogen-activated protein kinase

MEK

mitogen-activated protein kinase kinase

MRI

magnetic resonance imaging

MCI

Molecular Characterization Initiative

MET

Mesenchymal epithelial transition factor

MYB

myeloblastosis viral oncogene

MYB-L1

myeloblastosis viral oncogene homolog-like 1

MYC

myelocytomatosis viral oncogene

NCI

National Cancer Institute

NF1

Neurofibromatosis type 1

NTRK

Neurotrophic tyrosine receptor kinase

OS

overall survival

PARP

poly-ADP ribose polymerase

PBTC

Pediatric Brain Tumor Consortium

pHGG

Pediatric high-grade glioma

pLGG

pediatric low-grade gliomas

PFA

posterior fossa A

PFB

posterior fossa B

PFS

progression-free survival

PR

Partial response

RNA

ribonucleic acid

RTPS

Rhabdoid Tumor Predisposition Syndrome

RT

radiation therapy

RTK

receptor tyrosine kinase

ROS

c-ros oncogene

SHH

Sonic hedgehog

SIOP-E

Society of Pediatric Oncology- Europe

SMARC A4

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4

SMARC B1

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1

SMO

smoothened

SWI/SNF

SWItch/Sucrose Non-Fermentable

TMZ

temozolomide

TP53

Tumor protein 53

WHO

World Health Organization

wnt

Wingless/Integrated

YAP

Yes-associated protein

ZFTA

Zinc Finger Translocation Associated

Footnotes

Conflicts of Interest: Jason Fangusaro serves on the pediatric advisory boards for AstraZenica, DayOne and Merck. All other authors have no conflicts of interest.

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