Paediatric low-grade glioma
Paediatric low-grade gliomas are slow-growing brain tumours driven almost always by a single overactive signal, the MAPK pathway, most often through a BRAF gene change. Because the switch is known, pills that block it (dabrafenib with trametinib, and tovorafenib) now shrink tumours far more often than chemotherapy, and children are increasingly spared radiation to the developing brain.
Overview
Paediatric low-grade glioma (pLGG) is a family of WHO grade 1 and 2 tumours (pilocytic astrocytoma, ganglioglioma, diffuse astrocytoma, pleomorphic xanthoastrocytoma and others) that is biologically distinct from adult glioma: it is a single-pathway disease. The KIAA1549-BRAF fusion is the most common driver, BRAF V600E the second, with NF1 loss, FGFR1 alterations and other RAS-MAPK lesions accounting for most of the rest. Tumours rarely transform, but they sit in places (optic pathway, hypothalamus, brainstem, thalamus) where surgery cannot remove them and where growth costs vision, hormones and cognition. Children with neurofibromatosis type 1 make up a large minority of optic pathway gliomas.
Complete resection is curative where it is possible. For unresectable or progressive disease the historical standard was carboplatin and vincristine (or vinblastine monotherapy), chosen so that radiotherapy could be deferred or avoided in young children. The field has now moved to pathway inhibition. In the phase 2 TADPOLE trial (NEJM 2023) dabrafenib plus trametinib produced far more responses and longer progression-free survival than carboplatin-vincristine in BRAF V600E tumours, leading to the first FDA approval of a targeted first-line therapy for a childhood glioma in March 2023. The type II RAF inhibitor tovorafenib, which works on BRAF fusions as well as V600E, produced durable responses in relapsed disease in FIREFLY-1 (Nature Medicine 2024) and received FDA accelerated approval in April 2024; FIREFLY-2/LOGGIC is testing it first line against chemotherapy. The MEK inhibitor selumetinib showed activity in the PBTC-029 studies and is being compared with carboplatin-vincristine in the COG trials ACNS1831 (NF1) and ACNS1833 (non-NF1).
The reframing is from a cancer to be eradicated to a chronic condition to be controlled while the brain matures: the open questions are how long to treat, whether tumours regrow when inhibitors stop, the long-term effects of MAPK inhibition on growth and bone, and how to protect vision in optic pathway tumours. Molecular diagnosis at presentation (fusion and point-mutation testing, methylation profiling) is now the standard entry point to care.
State of the art today
- pLGG is a single-pathway (RAS-MAPK) disease in almost every case; molecular testing at diagnosis now decides therapy.
- Targeted therapy has displaced chemotherapy for BRAF V600E tumours (dabrafenib plus trametinib) and gives a second option for fusion-driven tumours (tovorafenib); FIREFLY-2/LOGGIC tests tovorafenib first line.
- Radiotherapy is deferred or avoided in young children because of its cost to cognition, vision and endocrine function; proton therapy is used when radiation cannot be avoided.
- The disease is increasingly managed as a chronic condition: the aim is to preserve vision, hormones and learning through childhood, not only to shrink the tumour.
Where it starts and where it drains
Gliomas infiltrate along white matter and can cross the corpus callosum, medulloblastoma sits in the cerebellum, and CNS lymphoma favours deep periventricular tissue; none spread through lymph nodes.
- Frontal lobe (glioblastoma commonest)
- Temporal lobe
- Corpus callosum (butterfly glioma)
- Lower-grade IDH-mutant gliomaPilocytic astrocytoma (KIAA1549-BRAF fusion in most) · Ganglioglioma and pleomorphic xanthoastrocytoma (often BRAF V600E) · Diffuse astrocytoma, MYB or MYBL1-altered · Subependymal giant cell astrocytoma (tuberous sclerosis; mTOR inhibitors)
- Cerebellum (medulloblastoma)
- Brainstem (diffuse midline glioma)
- Ventricles and ependymal lining (ependymoma)
- Sella and pituitary (pituitary tumours, craniopharyngioma)
- Deep periventricular tissue (CNS lymphoma)
No conventional lymphatics: gliomas spread along white matter tracts and, rarely, through cerebrospinal fluid; medulloblastoma can seed the spine.
Same organ: Glioma & glioblastoma, Primary CNS lymphoma, Medulloblastoma, Diffuse midline glioma, H3 K27-altered (including DIPG), Atypical teratoid/rhabdoid tumour (ATRT), Ependymoma, Craniopharyngioma, Pituitary tumours (pituitary neuroendocrine tumours) and pituitary carcinoma
The most common brain tumour of childhood, roughly a third of all paediatric central nervous system tumours (NCI PDQ); many children live for decades with the disease.
- DNA methylation profilingEstablished
- AI in radiologyEstablished
- cfDNA fragmentomicsEstablished
- Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)Standard of care
- HCC surveillance in cirrhosis (ultrasound + AFP)Standard of care
- High-risk pancreatic surveillance (CAPS / PRECEDE)Established
- A 28-day national pathway for people with a positive multi-cancer blood test
- A breath test to rule out cancer in people with vague symptoms
- A cancer blood test for older people arriving at A&E with unexplained symptoms
- A legislated, publicly reported 28-day standard from urgent referral to diagnosis
- A live national dashboard of stage at diagnosis as the scorecard for early detection
- A single 'cancer check at 60' appointment bundling all screening tests
Background: Alpha-fetoprotein (AFP), Barrett's oesophagus, CA 19-9, Early detection, Faecal immunochemical test (FIT). Also on OnCo: Symptoms and red flags · Early detection roadmap.
Where the cases are
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
Maximal safe resection; gross total resection is curative in most and no adjuvant therapy is given. Observation for stable residual disease.
Dabrafenib plus trametinib first line (TADPOLE: higher response rate and longer progression-free survival than carboplatin-vincristine; FDA approval March 2023 for patients aged one year and over).
Tovorafenib (FIREFLY-1; FDA accelerated approval April 2024 for patients aged six months and over), or a MEK inhibitor such as selumetinib in trials.
Carboplatin and vincristine, or weekly vinblastine, to defer radiotherapy; focal conformal or proton radiotherapy is reserved for older children and for progression after systemic options.
Subtypes & biomarkers
top- Pilocytic astrocytoma (KIAA1549-BRAF fusion in most)
- Ganglioglioma and pleomorphic xanthoastrocytoma (often BRAF V600E)
- NF1-associated optic pathway glioma
- Diffuse astrocytoma, MYB or MYBL1-altered
- FGFR1-altered glioma (dysembryoplastic neuroepithelial tumour, rosette-forming glioneuronal tumour)
- Subependymal giant cell astrocytoma (tuberous sclerosis; mTOR inhibitors)
- KIAA1549-BRAF fusion
- BRAF V600E (worse response to chemotherapy, target of BRAF/MEK inhibitors)
- NF1 germline status
- FGFR1 mutation or fusion
- CDKN2A deletion (with V600E, marks higher risk)
- Methylation-based classification
- Visual acuity and visual fields in optic pathway glioma
Target prevalence in this cancer
- 1993Carboplatin-vincristine established for progressive childhood low-grade glioma
Packer and colleagues show chemotherapy can defer radiotherapy in young children.
- 2008KIAA1549-BRAF fusion discovered
Tandem duplication at 7q34 found in most pilocytic astrocytomas (Jones and colleagues), defining pLGG as a MAPK-pathway disease.
- 2019Selumetinib active in recurrent pLGG
PBTC-029 phase 2 (Fangusaro, Lancet Oncology) reports responses in BRAF-altered and NF1-associated tumours.
- 2023TADPOLE: dabrafenib plus trametinib beats chemotherapy first line
Higher response rate and longer progression-free survival than carboplatin-vincristine in BRAF V600E pLGG (NEJM); FDA approval in March 2023.
- 2024Tovorafenib approved for relapsed BRAF-altered pLGG
FIREFLY-1 (Nature Medicine 2024) shows durable responses across fusions and V600E; FDA accelerated approval April 2024.
Open problems, and what is being done about each
How long to continue MAPK inhibitors and whether tumours regrow on stopping; intermittent dosing and stop rules are being studied in FIREFLY-2 and the COG selumetinib trials.
Long-term effects of RAF and MEK inhibition on growth plates, skin and heart in children who may take them for years; registries and trial follow-up are collecting these data.
Preserving vision in optic pathway glioma, where imaging response and visual outcome do not always agree; visual endpoints are now built into trials.
Access to molecular testing and to the new drugs outside high-income countries.
and how the field plans to fix it →What is being done about thisCost and accessAvailable now- HPV & HBV vaccinationStandard of care
- ImatinibApproved
- Trastuzumab biosimilarsApproved
In trials- Gefitinib vs gefitinib plus pemetrexed-carboplatin in EGFR-mutant lung cancer (Tata Memorial)Positive
- IARC India HPV vaccine dose study (one, two or three doses)Positive
- IMAGINE (varnimcabtagene autoleucel, Immuneel)Positive
- Low-dose nivolumab plus metronomic chemotherapy (Tata Memorial)Positive
- Low-dose olanzapine for cancer anorexia (Tata Memorial)Positive
- METRO PLUS (Tata Memorial Centre, Varanasi)Positive
Ideas and roadmaps- 90-day reliance approval for cancer drugs cleared by two stringent regulators
- A cheap old tablet to restore appetite
- A combination pricing rule so two-drug regimens are not priced as two monopolies
- A coordinated reserve and shared schedule for the world's medical isotope reactors
- A dedicated global financing window for cancer, modelled on the Global Fund
- A delinked market-entry reward paid by payers when a repurposed generic wins approval
Background: Accelerated approval, Biosimilar, Real-world evidence. Also on OnCo: Financial help and assistance navigator · Coverage by country · HTA decisions.
Trials
topRecruiting now (live from ClinicalTrials.gov)
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Landmark trials in OnCo
Expert centres
topCentres linked to this cancer in OnCo
- via Proton therapy
- via Proton therapy
- via Proton therapy
- via DNA methylation profiling
- via Proton therapy
- via Proton therapy
- via DNA methylation profiling, Proton therapy
- Children's Oncology Group (COG)Monrovia, CA, USvia this cancer, NCI-COG Pediatric MATCH (APEC1621)
- Innovative Therapies for Children with Cancer (ITCC)Villejuif, FRvia this cancer, NCI-COG Pediatric MATCH (APEC1621)
- Aarhus University HospitalAarhus, DKvia Proton therapy
- ACCELERATEBrussels, BEvia this cancer
- via Proton therapy
- Alliance for Clinical Trials in OncologyChicago, IL, USvia Carboplatin
- American Society for Radiation OncologyArlington, VA, USvia Proton therapy
- Apollo Hospitals (Apollo Cancer Centres)Chennai, INvia Proton therapy
- via Proton therapy
- Centre Antoine LacassagneNice, FRvia Proton therapy
- Centre François BaclesseCaen, FRvia Proton therapy
- Chang Gung Memorial HospitalTaoyuan, TWvia Proton therapy
- Children's Cancer and Leukaemia GroupLeicester, GBvia this cancer
- Children's Hospital of PhiladelphiaPhiladelphia, PA, USvia Proton therapy
- Cleveland Clinic Abu DhabiAbu Dhabi, AEvia Proton therapy
- via Proton therapy
- Erasmus MC Cancer InstituteRotterdam, NLvia Proton therapy
- European Society for Radiotherapy and OncologyBrussels, BEvia Proton therapy
- via DNA methylation profiling
- German Breast Group (GBG)Neu-Isenburg, DEvia Carboplatin
- German Cancer Research Center (DKFZ)Heidelberg, DEvia DNA methylation profiling
- Histiocyte SocietyPitman, USvia Vinblastine
- Hokkaido University HospitalSapporo, JPvia Proton therapy
- Institute of Oncology LjubljanaLjubljana, SIvia Carboplatin
- via DNA methylation profiling
- via Proton therapy
- Leiden University Medical CenterLeiden, NLvia Proton therapy
- Maastricht UMC+ Comprehensive Cancer CenterMaastricht, NLvia Proton therapy
- via Proton therapy
- via Proton therapy
- via Proton therapy
- via Proton therapy
- National Cancer Center Hospital EastKashiwa, Chiba, JPvia Proton therapy
- National Cancer Center KoreaGoyang, KRvia Proton therapy
- National Cancer Centre SingaporeSingapore, SGvia Proton therapy
- National Cancer Institute (NIH)Bethesda, MD, USvia NCI-COG Pediatric MATCH (APEC1621)
- National Taiwan University HospitalTaipei, TWvia Proton therapy
- via Proton therapy
- via Proton therapy
- via Proton therapy
- via DNA methylation profiling
- via Proton therapy
- Royal Adelaide HospitalAdelaide, AUvia Proton therapy
- Ruijin Hospital, Shanghai Jiao Tong UniversityShanghai, CNvia Proton therapy
- via Proton therapy
- Shizuoka Cancer CenterNagaizumi, Shizuoka, JPvia Proton therapy
- via this cancer
- via Proton therapy
- via DNA methylation profiling
- via Proton therapy
- The Clatterbridge Cancer Centre NHS Foundation TrustLiverpool, GBvia Proton therapy
- via Proton therapy
- via Proton therapy
- via Proton therapy
- via Proton therapy
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterBaltimore, MD, USNCI comprehensivevia Proton therapy
- via Proton therapy
- via DNA methylation profiling
- UZ Leuven / Leuven Cancer InstituteLeuven, BEvia Proton therapy
- Wellcome Sanger InstituteHinxton, GBvia BRAF
- via Proton therapy
- Zhejiang Cancer HospitalHangzhou, CNvia Proton therapy
Questions to ask
topQuestions to ask your oncologist about Paediatric low-grade glioma
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example KIAA1549-BRAF fusion, BRAF V600E, NF1 germline status, FGFR1 mutation or fusion, CDKN2A deletion), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Pilocytic astrocytoma, Ganglioglioma and pleomorphic xanthoastrocytoma, NF1-associated optic pathway glioma.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Resectable tumour
- For my situation (resectable tumour), which of the standard options do you recommend and why?Why: Guideline options include: Maximal safe resection; gross total resection is curative in most and no adjuvant therapy is given. Observation for stable residual disease.
Unresectable or progressive, BRAF V600E
- For my situation (unresectable or progressive, braf v600e), which of the standard options do you recommend and why?Why: Guideline options include: Dabrafenib plus trametinib first line (TADPOLE: higher response rate and longer progression-free survival than carboplatin-vincristine; FDA approval March 2023 for patients aged one year and over).
- Am I a candidate for Dabrafenib + trametinib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of TADPOLE (CDRB436G2201) apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Relapsed or refractory, BRAF fusion or V600E
- For my situation (relapsed or refractory, braf fusion or v600e), which of the standard options do you recommend and why?Why: Guideline options include: Tovorafenib (FIREFLY-1; FDA accelerated approval April 2024 for patients aged six months and over), or a MEK inhibitor such as selumetinib in trials.
- Am I a candidate for Tovorafenib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of FIREFLY-1 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Unresectable, no targetable alteration or targeted drug unavailable
- For my situation (unresectable, no targetable alteration or targeted drug unavailable), which of the standard options do you recommend and why?Why: Guideline options include: Carboplatin and vincristine, or weekly vinblastine, to defer radiotherapy; focal conformal or proton radiotherapy is reserved for older children and for progression after systemic options.
- Am I a candidate for Carboplatin, Vincristine, Vinblastine, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of Tovorafenib, Dabrafenib + trametinib, FIREFLY-1, DNA methylation profiling?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “How long to continue MAPK inhibitors and whether tumours regrow on stopping; intermittent dosing and stop rules are being studied in FIREFLY-2 and the COG selumetinib trials”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Long-term effects of RAF and MEK inhibition on growth plates, skin and heart in children who may take them for years; registries and trial follow-up are collecting these data”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
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Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
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3bottlenecks
2Latest papers
topQuery for this cancer: (TITLE:"Paediatric low-grade glioma" OR ABSTRACT:"Paediatric low-grade glioma" OR TITLE:"Childhood astrocytoma" OR ABSTRACT:"Childhood astrocytoma" OR TITLE:"pLGG" OR ABSTRACT:"pLGG" OR TITLE:"Pilocytic astrocytoma" OR ABSTRACT:"Pilocytic astrocytoma" OR TITLE:"Optic pathway glioma" OR ABSTRACT:"Optic pathway glioma" OR TITLE:"Childhood glioma low grade" OR ABSTRACT:"Childhood glioma low grade") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Paediatric low-grade glioma, not a curated reading list.
Pages like this
not linked directly; found by shared links- CancerAtypical teratoid/rhabdoid tumour (ATRT)
Shares NCI-COG Pediatric MATCH (APEC1621), Late effects and survivorship toxicity, SIOP Europe – European Society for Paediatric Oncology, Vincristine and the tags nci-coverage, paediatric, cns.
- TrialACTION
Shares RACE for Children Act, Diffuse midline glioma, H3 K27-altered (including DIPG), Rare and paediatric cancers without markets and the tags nci-coverage, paediatric, cns.
- TrialCOG ACNS0331
Shares Late effects and survivorship toxicity, Vincristine, Children's Oncology Group (COG), Survivorship and late effects are neglected and the tags nci-coverage, paediatric, cns.
- CancerLangerhans cell histiocytosis (LCH)
Shares Vinblastine, Late effects and survivorship toxicity, SIOP Europe – European Society for Paediatric Oncology, Dabrafenib + trametinib and the tags nci-coverage, paediatric.
- CancerGerm cell tumours of childhood and adolescence (extracranial and CNS)
Shares Children's Cancer and Leukaemia Group, Late effects and survivorship toxicity, SIOP Europe – European Society for Paediatric Oncology, Survivorship care and late-effects surveillance and the tags nci-coverage, paediatric.
- InstitutionHistiocyte Society
Shares Vinblastine, Rare and paediatric cancers without markets and the tags nci-coverage, paediatric.
- CancerRare cancers of childhood (NCI PDQ umbrella)
Shares Children's Cancer and Leukaemia Group, RACE for Children Act, NCI-COG Pediatric MATCH (APEC1621), SIOP Europe – European Society for Paediatric Oncology and the tags nci-coverage, paediatric.
- CancerChildhood lung and airway tumours (pleuropulmonary blastoma, tracheobronchial tumours)
Shares SIOP Europe – European Society for Paediatric Oncology, Vincristine, Children's Oncology Group (COG), Germline (hereditary) testing and the tags nci-coverage, paediatric.