{"entity":{"id":"paediatric-low-grade-glioma","kind":"cancer","name":"Paediatric low-grade glioma","aka":["Childhood astrocytoma","pLGG","Pilocytic astrocytoma","Optic pathway glioma","Childhood glioma (low grade)"],"tldr":"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.","summary":"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.\n\nComplete 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).\n\nThe 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.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Pilocytic_astrocytoma","links":[{"label":"NCI PDQ: childhood astrocytomas, other gliomas and glioneuronal tumours","url":"https://www.cancer.gov/types/brain/hp/child-astrocytoma-treament-pdq"},{"label":"TADPOLE: dabrafenib plus trametinib in BRAF V600E pLGG (NEJM 2023)","url":"https://doi.org/10.1056/NEJMoa2303815"},{"label":"FIREFLY-1: tovorafenib in relapsed BRAF-altered pLGG (Nature Medicine 2024)","url":"https://doi.org/10.1038/s41591-023-02668-y"}],"tags":["nci-coverage","paediatric","cns"],"related":["dipg-dmg","glioblastoma","race-for-children-act","ependymoma","craniopharyngioma","idh-mutant-astrocytoma","oligodendroglioma","paediatric-high-grade-glioma"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","methylation-profiling","proton-therapy","mri","survivorship-care-plan"],"targets":["braf"],"drugs":["dabrafenib-trametinib","tovorafenib","carboplatin","vincristine","vinblastine"],"companies":["day-one-biopharmaceuticals","novartis","childrens-oncology-group","cclg"],"institutions":["siop-europe"],"pathways":["ras-mapk","glioma-signalling"],"terms":["late-effects","germline-testing"],"trials":["tadpole","firefly-1","pediatric-match"],"people":[],"bottlenecks":["b-rare-cancers","b-survivorship"],"keyPapers":["paper-kilburn-nat-med","paper-bouffet-n-engl-j-med"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"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.","subtypes":["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)"],"biomarkers":["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"],"standardOfCare":[{"setting":"Resectable tumour","approach":"Maximal safe resection; gross total resection is curative in most and no adjuvant therapy is given. Observation for stable residual disease.","refs":["mri"],"guideline":{"version":"NCI PDQ: childhood astrocytomas, other gliomas and glioneuronal tumours","url":"https://www.cancer.gov/types/brain/hp/child-astrocytoma-treament-pdq"}},{"setting":"Unresectable or progressive, BRAF V600E","approach":"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).","refs":["dabrafenib-trametinib","tadpole"],"guideline":{"version":"FDA label 2023; NCI PDQ"}},{"setting":"Relapsed or refractory, BRAF fusion or V600E","approach":"Tovorafenib (FIREFLY-1; FDA accelerated approval April 2024 for patients aged six months and over), or a MEK inhibitor such as selumetinib in trials.","refs":["tovorafenib","firefly-1"],"guideline":{"version":"FDA accelerated approval 2024"}},{"setting":"Unresectable, no targetable alteration or targeted drug unavailable","approach":"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.","refs":["carboplatin","vincristine","vinblastine","proton-therapy"],"guideline":{"version":"NCI PDQ; SIOPE LGG guidance"}}],"stateOfArt":["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."],"history":[{"year":1993,"title":"Carboplatin-vincristine established for progressive childhood low-grade glioma","note":"Packer and colleagues show chemotherapy can defer radiotherapy in young children.","refs":["carboplatin","vincristine"]},{"year":2008,"title":"KIAA1549-BRAF fusion discovered","note":"Tandem duplication at 7q34 found in most pilocytic astrocytomas (Jones and colleagues), defining pLGG as a MAPK-pathway disease.","refs":["braf","ras-mapk"]},{"year":2019,"title":"Selumetinib active in recurrent pLGG","note":"PBTC-029 phase 2 (Fangusaro, Lancet Oncology) reports responses in BRAF-altered and NF1-associated tumours.","refs":[]},{"year":2023,"title":"TADPOLE: dabrafenib plus trametinib beats chemotherapy first line","note":"Higher response rate and longer progression-free survival than carboplatin-vincristine in BRAF V600E pLGG (NEJM); FDA approval in March 2023.","refs":["dabrafenib-trametinib","tadpole"]},{"year":2024,"title":"Tovorafenib approved for relapsed BRAF-altered pLGG","note":"FIREFLY-1 (Nature Medicine 2024) shows durable responses across fusions and V600E; FDA accelerated approval April 2024.","refs":["tovorafenib","firefly-1"]}],"pipeline":["tovorafenib","dabrafenib-trametinib","firefly-1","methylation-profiling","proton-therapy"],"openProblems":["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."],"parent":"glioblastoma"},"route":"/cancers/paediatric-low-grade-glioma/","neighbours":{"cancer":[{"id":"idh-mutant-astrocytoma","kind":"cancer","name":"Astrocytoma, IDH-mutant (grades 2 to 4)","route":"/cancers/idh-mutant-astrocytoma/"},{"id":"brain-tumours","kind":"cancer","name":"Brain and spinal cord tumours (all types)","route":"/cancers/brain-tumours/"},{"id":"childhood-cancers","kind":"cancer","name":"Childhood cancers (all types)","route":"/cancers/childhood-cancers/"},{"id":"craniopharyngioma","kind":"cancer","name":"Craniopharyngioma","route":"/cancers/craniopharyngioma/"},{"id":"dipg-dmg","kind":"cancer","name":"Diffuse midline glioma, H3 K27-altered (including DIPG)","route":"/cancers/dipg-dmg/"},{"id":"ependymoma","kind":"cancer","name":"Ependymoma","route":"/cancers/ependymoma/"},{"id":"glioblastoma","kind":"cancer","name":"Glioma & glioblastoma","route":"/cancers/glioblastoma/"},{"id":"oligodendroglioma","kind":"cancer","name":"Oligodendroglioma, IDH-mutant and 1p/19q-codeleted","route":"/cancers/oligodendroglioma/"},{"id":"optic-pathway-glioma","kind":"cancer","name":"Optic pathway glioma","route":"/cancers/optic-pathway-glioma/"},{"id":"paediatric-high-grade-glioma","kind":"cancer","name":"Paediatric high-grade glioma (excluding diffuse midline glioma)","route":"/cancers/paediatric-high-grade-glioma/"}],"term":[{"id":"cdkn2a-homozygous-deletion","kind":"term","name":"CDKN2A/B homozygous deletion","route":"/terms/cdkn2a-homozygous-deletion/"},{"id":"late-effects","kind":"term","name":"Late effects and survivorship toxicity","route":"/terms/late-effects/"},{"id":"race-for-children-act","kind":"term","name":"RACE for Children Act","route":"/terms/race-for-children-act/"}],"technology":[{"id":"methylation-profiling","kind":"technology","name":"DNA methylation profiling","route":"/technologies/methylation-profiling/"},{"id":"rejuv-ayac-education-and-work","kind":"technology","name":"Education, work and the years that were interrupted","route":"/technologies/rejuv-ayac-education-and-work/"},{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"},{"id":"rejuv-paed-growth-and-height","kind":"technology","name":"Growth and final height after treatment in childhood, and growth hormone","route":"/technologies/rejuv-paed-growth-and-height/"},{"id":"intraoperative-mri-ct","kind":"technology","name":"Intraoperative MRI and CT","route":"/technologies/intraoperative-mri-ct/"},{"id":"litt-systems","kind":"technology","name":"Laser interstitial thermal therapy systems (NeuroBlate, Visualase)","route":"/technologies/litt-systems/"},{"id":"rejuv-paed-neurocognitive","kind":"technology","name":"Memory, attention and learning after treatment of a childhood cancer","route":"/technologies/rejuv-paed-neurocognitive/"},{"id":"mri","kind":"technology","name":"MRI","route":"/technologies/mri/"},{"id":"proton-therapy","kind":"technology","name":"Proton therapy","route":"/technologies/proton-therapy/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"survivorship-care-plan","kind":"technology","name":"Survivorship care and late-effects surveillance","route":"/technologies/survivorship-care-plan/"},{"id":"rejuv-paed-pituitary-and-puberty","kind":"technology","name":"The pituitary, puberty and the hypothalamic axis after cranial radiotherapy in childhood","route":"/technologies/rejuv-paed-pituitary-and-puberty/"},{"id":"transcranial-focused-ultrasound-systems","kind":"technology","name":"Transcranial focused ultrasound systems (Exablate Neuro, SonoCloud)","route":"/technologies/transcranial-focused-ultrasound-systems/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"fam174b","kind":"target","name":"FAM174B","route":"/targets/fam174b/"},{"id":"kdm3b","kind":"target","name":"KDM3B","route":"/targets/kdm3b/"},{"id":"lats2","kind":"target","name":"LATS2","route":"/targets/lats2/"},{"id":"ldb1","kind":"target","name":"LDB1","route":"/targets/ldb1/"},{"id":"myb","kind":"target","name":"MYB","route":"/targets/myb/"},{"id":"ppm1d","kind":"target","name":"PPM1D","route":"/targets/ppm1d/"},{"id":"prkar1a","kind":"target","name":"PRKAR1A","route":"/targets/prkar1a/"},{"id":"sufu","kind":"target","name":"SUFU","route":"/targets/sufu/"},{"id":"tcf4","kind":"target","name":"TCF4","route":"/targets/tcf4/"}],"drug":[{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"dabrafenib","kind":"drug","name":"Dabrafenib","route":"/drugs/dabrafenib/"},{"id":"dabrafenib-trametinib","kind":"drug","name":"Dabrafenib + trametinib","route":"/drugs/dabrafenib-trametinib/"},{"id":"tovorafenib","kind":"drug","name":"Tovorafenib","route":"/drugs/tovorafenib/"},{"id":"trametinib","kind":"drug","name":"Trametinib","route":"/drugs/trametinib/"},{"id":"vinblastine","kind":"drug","name":"Vinblastine","route":"/drugs/vinblastine/"},{"id":"vincristine","kind":"drug","name":"Vincristine","route":"/drugs/vincristine/"}],"company":[{"id":"cclg","kind":"company","name":"Children's Cancer and Leukaemia Group","route":"/companies/cclg/"},{"id":"childrens-oncology-group","kind":"company","name":"Children's Oncology Group (COG)","route":"/companies/childrens-oncology-group/"},{"id":"day-one-biopharmaceuticals","kind":"company","name":"Day One Biopharmaceuticals","route":"/companies/day-one-biopharmaceuticals/"},{"id":"itcc","kind":"company","name":"Innovative Therapies for Children with Cancer (ITCC)","route":"/companies/itcc/"},{"id":"novartis","kind":"company","name":"Novartis","route":"/companies/novartis/"}],"institution":[{"id":"accelerate-platform","kind":"institution","name":"ACCELERATE","route":"/institutions/accelerate-platform/"},{"id":"siop-europe","kind":"institution","name":"SIOP Europe (European Society for Paediatric Oncology)","route":"/institutions/siop-europe/"}],"pathway":[{"id":"glioma-signalling","kind":"pathway","name":"Glioma (KEGG map)","route":"/pathways/glioma-signalling/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"trial":[{"id":"nct05566795","kind":"trial","name":"DAY101 vs. Standard of Care Chemotherapy in Pediatric Participants With Low-Grade Glioma Requiring First-Line Systemic Therapy (LOGGIC/FIREFLY-2)","route":"/trials/nct05566795/"},{"id":"firefly-1","kind":"trial","name":"FIREFLY-1","route":"/trials/firefly-1/"},{"id":"pediatric-match","kind":"trial","name":"NCI-COG Pediatric MATCH (APEC1621)","route":"/trials/pediatric-match/"},{"id":"tadpole","kind":"trial","name":"TADPOLE (CDRB436G2201)","route":"/trials/tadpole/"}],"bottleneck":[{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"},{"id":"b-survivorship","kind":"bottleneck","name":"Survivorship and late effects are neglected","route":"/bottlenecks/b-survivorship/"}],"paper":[{"id":"paper-bouffet-n-engl-j-med","kind":"paper","name":"Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations","route":"/key-papers/paper-bouffet-n-engl-j-med/"},{"id":"paper-kilburn-nat-med","kind":"paper","name":"The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial","route":"/key-papers/paper-kilburn-nat-med/"}],"biomarker":[{"id":"braf-fusion","kind":"biomarker","name":"BRAF fusion or rearrangement","route":"/biomarkers/braf-fusion/"},{"id":"braf-v600e","kind":"biomarker","name":"BRAF V600E (and V600K)","route":"/biomarkers/braf-v600e/"}],"roadmap":[{"id":"paediatric-oncology-roadmap","kind":"roadmap","name":"Paediatric oncology roadmap: cooperative-group cures → engineered immunity → drugs developed for children first","route":"/roadmaps/paediatric-oncology-roadmap/"}],"journal":[{"id":"brain-tumor-pathology","kind":"journal","name":"Brain tumor pathology","route":"/journals/brain-tumor-pathology/"},{"id":"cns-oncology","kind":"journal","name":"CNS oncology","route":"/journals/cns-oncology/"},{"id":"journal-of-neuro-oncology","kind":"journal","name":"Journal of neuro-oncology","route":"/journals/journal-of-neuro-oncology/"}]}}