Version July 2025
INTRODUCTION —
Central nervous system (CNS) tumors are the second most common childhood cancer and are responsible for the highest number of cancer-related deaths in children and adolescents. Pediatric low-grade gliomas (PLGGs) are the most common pediatric CNS tumor and include World Health Organization (WHO) grade 1 and 2 gliomas, glioneuronal tumors, and neuronal tumors.
PLGGs are a diverse group of tumors that can arise anywhere in the neuroaxis and have widely variable clinical presentations and treatment courses. Mortality from PLGGs is generally low. However, approximately half will recur or progress and, as a result, can be associated with significant morbidity, decreased functional outcomes, and decreased quality of life.
Historically, treatment of PLGGs has involved surgery, conventional chemotherapy, and/or radiation therapy (RT). However, since the discovery that PLGGs are largely a single pathway disease with upregulation of the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway, molecular features have become important in both diagnosis and treatment of PLGGs, and targeted therapies are becoming a standard of care for many tumors.
This topic will provide an overview of the epidemiology, clinical features, diagnosis, and management of PLGGs. High-grade gliomas in infants and children are reviewed separately. (See "Infant-type hemispheric gliomas" and "High-grade gliomas in children and adolescents".)
EPIDEMIOLOGY —
Pediatric low-grade gliomas (PLGGs) make up approximately 30 to 40 percent of pediatric central nervous system (CNS) tumors, making them the most common pediatric CNS tumor [1-4].
The annual incidence of PLGGs in the United States is 1.3 to 2.1 per 100,000 persons [5]. The most common PLGG, pilocytic astrocytoma (PA), has an incidence of approximately 1 per 100,000 persons [6]. The true global burden of PLGGs is unknown [7]. (See "Epidemiology and classification of central nervous system tumors in children".)
The median age at diagnosis of PLGG is approximately seven years, but they can occur at any age. The median age varies by location and underlying molecular alteration. PLGGs arising in the cerebral hemispheres tend to be seen in older children (median age of 10 years), while other locations tend to occur at younger ages [8].
RISK FACTORS —
Most pediatric low-grade gliomas (PLGGs) are sporadic. However, some are associated with cancer predisposition syndromes, most notably neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC).
Neurofibromatosis 1 — NF1 is the most common heritable cancer predisposition syndrome and arises from a germline pathogenic variant in the tumor suppressor gene, neurofibromin 1 (NF1). NF1 is characterized by café-au-lait macules, axillary and/or inguinal freckling, neurofibromas, and other clinical findings. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)
Among patients with NF1, 10 to 15 percent develop an optic pathway glioma (OPG) and 3 to 5 percent develop a low-grade glioma outside of the optic pathway [2]. Among all patients with PLGGs, approximately 15 percent have NF1 [8]. This proportion increases significantly, to 59 to 70 percent, in patients with OPG [2,9-12].
Tuberous sclerosis complex — TSC is an inherited neurocutaneous disorder caused by pathogenic variants in the tuberous sclerosis complex subunit 1 (TSC1) or 2 (TSC2) genes, which lead to mechanistic target of rapamycin (mTOR) pathway overactivation and tumor formation. Clinical features include the development of benign tumors in multiple organs, characteristic skin lesions, epilepsy, and/or neurocognitive deficits. The characteristic PLGG associated with TSC is subependymal giant cell astrocytoma (SEGA), which occurs in 6 to 9 percent of patients with TSC [13-15]. (See "Tuberous sclerosis complex: Clinical features".)
CLINICAL FEATURES
Signs and symptoms — Presenting signs and symptoms of pediatric low-grade gliomas (PLGGs) are highly dependent on tumor location (table 1) and patient age (table 2). PLGGs tend to be indolent tumors, and symptoms can develop slowly over time. Common presenting symptoms are consistent with other pediatric brain tumors: headache, vomiting, seizures, changes in vision, and fatigue [16]. Patients with cerebellar or midline tumors can present with cerebellar symptoms or signs of increased intracranial pressure secondary to obstructive hydrocephalus. (See "Clinical manifestations and diagnosis of central nervous system tumors in children", section on 'Common presenting signs and symptoms'.)
The diencephalon is a common location for PLGGs. Such tumors may present with diencephalic syndrome, a rare but life-threatening syndrome characterized by failure to thrive, often to the point of severe emaciation despite adequate caloric intake [17,18]. Locomotor hyperactivity and neurologic symptoms such as nystagmus or strabismus can also be seen.
Tumor location — PLGGs can occur anywhere in the brain or spine. The most common sites are cerebellum, diencephalon, and cerebral hemispheres. Less frequent locations include deep midline structures, brainstem, and spine [8]. Widely disseminated PLGGs are rare.
DIAGNOSTIC EVALUATION —
Diagnosis of pediatric low-grade gliomas (PLGGs) requires neuroimaging, histopathologic evaluation, and molecular testing. Lumbar puncture and cytologic evaluation of the cerebrospinal fluid are not required for diagnosis unless the evaluation suggests the presence of disseminated disease.
Neuroimaging — Imaging plays an important role in the initial identification of a brain tumor, surgical planning, and subsequent surveillance after completion of therapy. Magnetic resonance imaging (MRI) of the brain with and without contrast is the preferred imaging modality for all brain tumors, including PLGGs. Young children require sedation under anesthesia for MRI, while older children often tolerate routine imaging without sedation.
MRI provides important information on tumor location, size, margins, and signal characteristics. PLGGs are often well-circumscribed masses that are hypointense on T1-weighted sequences, hyperintense on T2 and fluid-attenuated inversion recovery (FLAIR) sequences, and associated with little to no surrounding edema. Tumors can be solid and/or cystic with variable enhancement patterns (image 1 and image 2); they do not typically show evidence of restricted diffusion on diffusion-weighted sequences (image 3 and image 4). Tumors with cysts may have associated enhancing mural nodules. Calcifications can be seen [19,20].
PLGGs have low potential to spread throughout the neuroaxis, and MRI of the spine is not required unless there is concern for disseminated disease based on symptoms (eg, unexplained leg pain or weakness, back pain, or bowel and bladder dysfunction).
Tissue diagnosis — Neuroimaging is not able to distinguish histologic grade and type of PLGG, and tissue is required for definitive diagnosis. The main exceptions are optic pathway glioma (OPG) and typical-appearing tectal glioma, which can be diagnosed with imaging alone. Biopsy is typically performed at the time of a definitive surgical procedure. (See 'Surgery' below.)
PATHOLOGY
Histologic and molecular features — Pediatric low-grade gliomas (PLGGs) are World Health Organization (WHO) grade 1 or 2 with rare mitotic activity and a low Ki-67 index (usually below 10 percent). They are well-differentiated tumors without hypercellularity or nuclear atypia (picture 1). Cellular appearance and other histopathologic features vary by tumor type [20].
PLGGs almost universally involve aberrant activation of a single pathway, the RAS/mitogen-activated protein kinase (MAPK) pathway, and in most cases, a single-driver genetic alteration is identified [1,2,8]. In a study of over 1000 PLGGs, 84 percent had an identified driver mutation and 95 percent had evidence of upregulation of the RAS/MAPK pathway [8]. In contrast with adult-type diffuse gliomas, they typically do not harbor mutations in isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2).
Many mutations have been identified that cause upregulation of the RAS/MAPK pathway (table 3). BRAF alterations, including BRAF V600E mutations, KIAA1549-BRAF fusion, and other non-canonical BRAF fusions, are the most common and are seen in approximately 70 percent of sporadic cases. The second most common involve fibroblast growth factor receptor (FGFR) genes and include mutations or fusions in FGFR1 or FGFR2/3. Other known alterations include mutations in NF1, NTRK2, RAF1, ALK, ROS1, CRAF fusions, KRAS mutations, MAP2K1 alterations, and PTPN11 mutations [1,2,8].
Non-RAS/MAPK pathway alterations are less common. These include alterations in TSC1 and TSC2, which are implicated in tuberous sclerosis complex (TSC) and result in dysregulation of the PI3-kinase-AKT-mechanistic target of rapamycin (mTOR) pathway and alterations in MYB proto-oncogene, transcription factor (MYB) and MYB proto-oncogene like 1 (MYBL1) [1,2,8].
In rare cases, aberrations more commonly seen in high-grade gliomas, such as H3 K27M mutations or cyclin-dependent kinase inhibitor 2A (CDKN2A) deletions, are seen in PLGGs. However, they usually co-occur with other alterations, most commonly BRAF V600E mutation, and are associated with significantly worse prognosis [21]. (See 'Prognosis' below.)
In addition to molecular genetic testing, methylation and copy number profiles are being used with increasing frequency for accurate diagnosis.
Specific tumor types — As of the 2021 revision of the WHO Classification of Central Nervous System Tumours, tumors that have historically been called PLGGs are divided across three subcategories (table 4) [22,23]:
●Pediatric-type diffuse low-grade gliomas (table 5)
●Circumscribed astrocytic gliomas (table 6)
●Glioneuronal and neuronal tumors (table 7)
As more tumors undergo molecular testing, diagnostic patterns are emerging within and between specific tumor types (table 3) [2]. As examples:
●KIAA1549-BRAF fusion is the most frequent genetic alteration identified in pilocytic astrocytomas (PAs) and in PLGGs arising in the posterior fossa in general.
●BRAF V600E mutations make up a larger portion of pleomorphic xanthoastrocytomas (PXAs), diffuse astrocytomas, and gangliogliomas and are more likely to occur in supratentorial tumors.
●FGFR alterations are more frequently seen in dysembryoplastic neuroepithelial tumors (DNETs) and other glioneuronal tumors and also tend to occur more frequently in midline structures.
A few key PLGG tumor types are highlighted below. Diagnostic and management approaches discussed throughout the topic are applicable for these and other, less common PLGGs.
Pilocytic astrocytoma — PA is the most common non-neurofibromatosis type 1 (NF1) PLGG. In an analysis of 1000 patients with PLGGs, PAs made up 36 percent of non-NF1 cases, with a median age of diagnosis of 7.6 years (range 0 to 18.7 years) [8]. PAs are circumscribed tumors that often arise in the cerebellum (image 4) but can occur anywhere in the CNS. They are the most common non-NF1 PLGG in all CNS tumor locations except the cerebral hemispheres, where tumor types are more evenly represented [8].
On histopathology, PAs generally have low to moderate cellularity, with neoplastic cells that have variable morphology [23]. Some have a biphasic pattern made up of compact areas of bipolar cells and Rosenthal fibers alternating with loose, microcytic regions notable for oligodendrocyte-like cells. The most common gene alteration is the KIAA1549-BRAF fusion, found in approximately 60 percent of PAs.
Pleomorphic xanthoastrocytoma — PXAs are rare, circumscribed astrocytic tumors that predominantly arise in the supratentorial compartment, most commonly in the temporal lobe. As such, patients often present with a history of seizures.
On histopathology, PXAs are composed of a mixture of pleomorphic, multinucleated, spindled, and epithelioid cells that sometimes contain lipid droplets. Eosinophilic and pale granular bodies are also seen. These tumors generally have low mitotic activity, but some can demonstrate higher mitotic activity and anaplasia. PXAs are WHO grade 2 to 3, depending on histologic features [23]. The most common molecular alterations are CDKN2A/B deletions (>90 percent) and BRAF V600E mutations (60 to 80 percent) [2,8,23].
Desmoplastic infantile astrocytoma/ganglioglioma — Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are PLGGs occurring predominantly in infants. Tumors tend to arise in cerebral hemispheres and can be very large on presentation. A common presenting symptom can be increasing head circumference and bulging fontanelles.
On histopathology, these are biphasic tumors made up of prominent desmoplastic stroma mixed with neuroepithelial components. The most common mechanism of MAPK pathway activation in these tumors is by mutation or fusion involving BRAF or RAF1 [23].
Dysembryoplastic neuroepithelial tumor — DNETs are rare glioneuronal neoplasms that can arise anywhere in the cerebral cortex but tend to occur more frequently in the temporal or frontal lobes [2,8,23]. Most patients with DNETs present with focal epilepsy that has been refractory to medical management.
The key histopathology features for these tumors include entrapped cortical neurons, foci of dysplastic cortical organization, a multinodular architecture with components resembling astrocytoma or oligodendroglioma, and a columnar structure oriented perpendicular to the cortical surface [23]. Common molecular changes include alterations in FGFR1 (40 to 60 percent) and BRAF V600E mutations (up to 50 percent). Neither IDH1 nor IDH2 mutations are consistent with DNET, and the presence of either suggests a diffuse astrocytoma or oligodendroglioma. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors".)
Diffuse leptomeningeal glioneuronal tumor — Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare glioneuronal neoplasm that was first defined by the WHO Classification of Tumours in 2016 [23]. Although initially characterized as involving widespread leptomeningeal growth, some case reports and series have identified the presence of discrete, circumscribed tumors that precede the eventual diffuse leptomeningeal spread [24-26].
MRI findings differ from the more classic PLGG appearance and instead can show widespread leptomeningeal enhancement and thickening, often most prominent along the spinal cord, posterior fossa, and brainstem (image 5). Intraparenchymal and intramedullary enhancing nodules can also be seen. Clinical presentation is widely variable, but patients often present with signs and symptoms of increased intracranial pressure and obstructive hydrocephalus.
On histopathology, DLGNT has low to moderate cellularity and is made up of monomorphic oligodendrocyte-like tumor cells. These tumors are characterized by chromosome arm 1p-deletion, either alone or as 1p/19q codeletion (but without IDH1 or IDH2 mutations), and they often harbor KIAA1549-BRAF fusion [23].
DLGNTs have a tendency to be more refractory to treatments and have high rates of progression. As this is a newer entity, the etiology, natural history, and prognostic features are not yet well understood [23-26].
Others — Additional tumor types that are rarer or more evenly distributed among children and adults are reviewed separately. (See "Uncommon brain tumors".)
MANAGEMENT APPROACH —
Pediatric low-grade gliomas (PLGGs) vary widely in location, histologic subtype, and molecular alterations, and there is no standard treatment approach. Management is multimodal and, unless the tumor can be completely resected, usually requires use of cytotoxic chemotherapy, radiation therapy (RT), and/or targeted therapy. The goals of multidisciplinary care are to minimize treatment-related morbidities and maximize quality of life in addition to controlling the tumor.
Surgery — For all patients with operable PLGGs, we recommend maximal safe resection. Complete resection is the goal and is curative in most cases. Gross total resection (GTR) is the most favorable prognostic factor in observational studies of PLGGs across all tumor types, with 10-year progression-free survival exceeding 85 percent after a GTR compared with below 50 percent in patients with residual disease [1,2,8,27].
Complete surgical resection is not always possible, however, due to tumor location or degree of tumor infiltration. Resections of midline, optic pathway, and brainstem tumors pose much higher risk to the patient compared with posterior fossa and cerebral hemisphere resections. Even with subtotal resection, PLGGs have low mortality. Given this, aggressive surgeries that carry high risk to the patient should not be pursued.
When resection is not possible, except for optic pathway glioma (OPG) and typical-appearing tectal glioma, biopsy should be obtained for definitive diagnosis and identification of targetable molecular aberrations. Depending on the location of the tumor and surgeon preference, biopsies are performed stereotactically or during an open surgical procedure. Surgery also plays an adjunctive role in some cases for management of obstructive hydrocephalus, if present.
Monitoring after complete resection — Complete resection of a PLGG is curative in most cases, and no further therapy is required beyond surveillance to monitor for recurrence.
We typically obtain a brain MRI every three months for the first year. In the absence of recurrence or clinical concerns, MRIs can be spaced out to every four months in the second year, every six months in the third year, and then annually.
Residual/progressive tumors — For patients with PLGG that cannot be completely resected, adjuvant therapy is almost always required. Due to the indolent nature of PLGGs, however, there is no universally accepted guideline for when to intervene versus when to observe, and practice varies among providers. Timing of additional therapy is influenced by tumor location, size, the presence or absence of symptoms, and molecular features.
Once a decision is made to treat, selection depends on the tumor type and molecular aberration (if present), clinical trial availability and interest, regulatory approval status and cost (for targeted therapies), and individual patient factors that influence the balance of risks and benefits (eg, tumor size, location, and patient age when considering RT; age and comorbidities when considering systemic therapies).
Treatment strategies according to molecular subtype are outlined in the table (table 8). The approach for many tumors is in flux, with rapid advances in molecular diagnostics and discovery of targetable pathway alterations. All treatment decisions involve shared decision-making, and multidisciplinary case discussions are invaluable.
SPECIFIC THERAPIES
Chemotherapy — Conventional chemotherapy is a mainstay of treatment for pediatric low-grade gliomas (PLGGs) for tumors that cannot be completely resected surgically.
First-line regimens — In practice, carboplatin plus vincristine (CV) tends to be the preferred first-line chemotherapy in previously untreated PLGGs based on a balance of efficacy and tolerability (table 8). However, there are several other regimens that are accepted as first-line therapies, including thioguanine, procarbazine, lomustine, and vincristine (TPCV), vinblastine monotherapy, and carboplatin monotherapy, all with five-year progression-free survival ranging from approximately 35 to 45 percent in non-neurofibromatosis type 1 (NF1) PLGG [28-33].
The CV regimen has been examined in two multicenter cooperative group randomized trials in patients with newly diagnosed PLGG of varying histologies, completed prior to the 2021 revision of the World Health Organization (WHO) Classification of Central Nervous System Tumours. In both trials, CV resulted in similar outcomes as the comparator regimen and was better tolerated:
●In the Children's Oncology Group (COG) A9952 study, 274 children <10 years of age with previously untreated, progressive or residual low-grade glioma (LGG), were randomly assigned to receive CV or TPCV [28]. The most common tumor types were pilocytic astrocytoma (45 percent) and low-grade astrocytoma (20 percent). Five-year event-free survival (EFS) was nonsignificantly higher with TPCV (52 versus 39 percent, p = 0.10 for stratified log-rank test), and five-year overall survival (OS) was similar (87 versus 86 percent, p = 0.5). The TPCV regimen had higher toxicity.
●In the International Society of Pediatric Oncology-Low Grade Glioma (SIOP-LGG) 2004 study, 497 children ≤16 years of age (median 4.9 years) with previously untreated, progressive or residual LGG were randomly assigned to receive standard CV or CV plus etoposide [31]. Outcomes were similar between groups for both five-year progression-free survival (PFS; 46 versus 45 percent) and five-year OS (89 percent in both groups).
Evidence supporting monotherapy regimens in chemotherapy-naïve PLGG includes the following:
●Vinblastine – In a single-arm prospective multicenter study involving 54 patients with untreated, unresectable and/or progressive PLGG (median age 8 years), weekly vinblastine monotherapy was associated with five-year PFS and OS of 53 and 95 percent, respectively [30].
●Carboplatin – There are little prospective data on monthly carboplatin monotherapy in chemotherapy-naïve PLGGs, but retrospective studies have shown similar five-year PFS and OS compared with other first-line regimens [32-34].
Of note, across various PLGG trials, patients with NF1 tend to have superior EFS/PFS compared with patients who do not have NF1. This has been observed for the CV regimen in the COG A9952 study (five-year EFS 69 versus 39 percent) [29] and for vinblastine monotherapy (five-year PFS 85 versus 42 percent) [30].
All of the above chemotherapy regimens are associated with many toxicities including, but not limited to, myelosuppression, nausea/vomiting, hair loss, peripheral neuropathy, constipation, allergic reaction, and secondary malignancy.
Second-line regimens — Approximately 50 percent of patients will progress despite first-line chemotherapy and require additional therapy [28-32]. Such patients are at much higher risk of subsequent progressions and tend to be more resistant to additional chemotherapy [35].
There are several second-line chemotherapy regimens available, and selection is individualized. Examples include:
●Alternative first-line regimen – Any of the above regimens (CV, TPCV, vinblastine monotherapy, or carboplatin monotherapy) that were not used as first-line therapy can be used in the setting of progression. (See 'First-line regimens' above.)
●Other chemotherapy regimens – The combination of CV alternating with temozolomide was evaluated in patients with progressive or symptomatic PLGGs and was found to be feasible and safe [36].
●Bevacizumab-based therapy – Providers can also consider bevacizumab, alone or combined with irinotecan [33,34,37-40]. The use of bevacizumab has been associated with improved visual outcomes in patients with optic pathway glioma (OPG) experiencing visual deficits [37,39-41].
Radiation therapy — Radiation therapy (RT) is effective in treating PLGG, but there is no consensus on when and in whom it should be used. In general, with the availability of other therapies and the significant late effects associated with RT, RT is often delayed until the patient is older or is avoided altogether.
Historically, RT was used as first-line treatment for unresectable or progressive PLGGs with a 10-year PFS of approximately 70 percent [42-44]. RT is associated with significant side effects, however, including neurocognitive deficits, endocrine dysfunction, vascular abnormalities, secondary malignancy, and growth delays [45,46]. Frequency and severity are variable depending primarily on patient age, tumor location, and the presence of a cancer predisposition syndrome [47]. (See "Delayed complications of cranial irradiation".)
It is important to note that much of the long-term toxicity data in PLGG come from older trials performed before technology allowed for conformal radiation dose delivery. RT techniques have advanced significantly since that time with use of three-dimensional conformal techniques, intensity-modulated RT, and proton therapy. These techniques allow for more targeted approaches that spare surrounding normal tissue, and there are emerging data suggesting that proton RT results in fewer or less severe late effects and improved quality of life [48,49].
Additional long-term studies are needed to fully assess long-term toxicities with contemporary RT techniques. Systemic therapies, especially with the advent of targeted therapies, should continue to be considered as first-line for incompletely resected PLGGs. However, RT remains a safe and viable option for treatment of progressive PLGGs due to advances in RT and the ability to limit the field of radiation. This is especially true for patients who are experiencing rapid visual loss.
Targeted therapy — Development and testing of novel therapeutic agents that target the RAS/mitogen-activated protein kinase (MAPK) and mechanistic target of rapamycin (mTOR) pathways are rapidly expanding in PLGGs. Initial studies were performed in patients with recurrent and progressive PLGGs, but there are now several completed and ongoing studies evaluating these agents as first-line therapies.
BRAF inhibitors — Several BRAF inhibitors are available for use as monotherapy in patients with PLGG.
●Dabrafenib, vemurafenib – Dabrafenib and vemurafenib are first-generation BRAF inhibitors initially tested and approved for patients with melanoma harboring a BRAF V600E mutation. Subsequent studies have shown single-agent activity in patients with BRAF V600E-mutant PLGGs. They are not indicated in patients with other BRAF alterations (eg, KIAA-BRAF fusion) or BRAF-wildtype tumors due to the potential for paradoxical activation of RAS/MAPK signaling [50].
In a study of dabrafenib in 32 patients with relapsed or refractory BRAF V600E-mutant PLGG, the objective response rate was 44 percent, and one-year PFS was 85 percent [51]. The most common adverse events were fatigue, pyrexia, rash, and dry skin [51]. Notably, an increased risk of cutaneous squamous cell carcinoma has been described in patients treated with single-agent BRAF inhibitors. This risk is decreased significantly with dual BRAF/MEK inhibition [52,53]. (See 'Combination BRAF/MEK therapy' below.)
●Tovorafenib – Tovorafenib, a second-generation RAF inhibitor, was approved by the US Food and Drug Administration (FDA) in April 2024 for patients aged six months or older with relapsed or refractory PLGGs harboring BRAF alterations, including BRAF V600E mutations as well as BRAF fusions or rearrangements. Approval was based on the phase 2 FIREFLY-1 trial in 137 patients with relapsed/progressive BRAF-altered PLGG, which found an overall response rate of 67 percent and good tolerability [54]. The most common side effects were hair color change, elevations in creatine kinase (CK), anemia, fatigue, rash, growth failure, and intratumoral hemorrhage. Paradoxical activation of RAS/MAPK signaling has not been observed with tovorafenib or other second-generation RAF inhibitors in BRAF fusion- or rearrangement-positive PLGGs.
An ongoing open-label randomized phase 3 trial in patients without NF1 (FIREFLY-2) is investigating tovorafenib versus standard-of-care chemotherapy as first-line therapy for children with treatment-naïve, BRAF-altered LGG (NCT05566795) [55].
MEK inhibitors — There are several mitogen-activated protein kinase kinase (MEK) inhibitors that are at various stages of clinical testing in patients with PLGG.
●Selumetinib – Selumetinib is FDA-approved for treatment of plexiform neurofibromas in patients with NF1, and it also has activity in recurrent/progressive NF1-associated PLGGs as well as non-NF1-associated PLGGs with BRAF alterations, including fusions and BRAF V600E mutations [56,57]. Common side effects include rash, paronychia, and elevations in CK. Data in patients with OPG and/or NF1 are reviewed separately. (See "Optic pathway glioma", section on 'Role of MAPK pathway inhibition' and "Neurofibromatosis type 1 (NF1): Management and prognosis", section on 'Optic pathway gliomas and other low-grade gliomas'.)
There are two ongoing phase 3 trials comparing selumetinib with standard chemotherapy (CV) as first-line therapy in newly diagnosed patients with NF1-associated PLGG (NCT03871257) and non-NF1-associated PLGG (NCT04166409).
●Trametinib – Trametinib monotherapy has activity in BRAF-altered PLGGs and is FDA-approved in combination with dabrafenib for newly diagnosed BRAF V600E-mutant PLGG (see 'Combination BRAF/MEK therapy' below). As monotherapy, retrospective studies have noted objective response rates of approximately 20 to 30 percent and median response durations of 12 to 19 months in patients with recurrent or progressive PLGG harboring a range of BRAF alterations [58-61]. In a four-part phase 1/2 trial that included investigation of both trametinib monotherapy and trametinib plus dabrafenib in recurrent/progressive BRAF V600E-mutant PLGGs, the objective response rate was 15 percent in 13 patients who received trametinib monotherapy [62]. Treatment discontinuation for adverse effects was more common with monotherapy (54 versus 22 percent).
●Others – Other MEK inhibitors in various stages of clinical evaluation are binimetinib, cobimetinib, and mirdametinib [63].
Combination BRAF/MEK therapy — The combination of dabrafenib plus trametinib is approved by the FDA for children age one year and older with newly diagnosed BRAF V600E-mutant PLGG. The combination also has tissue-agnostic approval in patients ≥1 year of age with unresectable or metastatic BRAF V600E-mutant solid tumors that have progressed on previous treatment.
Approval for PLGG was based on results of an open-label randomized phase 2 trial comparing dabrafenib plus trametinib with CV as first-line therapy in 110 patients with treatment-naïve BRAF V600E-mutant PLGG [64]. The most common tumor types were pilocytic astrocytoma (30 percent), ganglioglioma (29 percent), and low-grade glioma not otherwise specified (19 percent). Compared with chemotherapy, targeted therapy resulted in a higher response rate (47 versus 11 percent), longer median PFS (20.1 versus 7.4 months), and fewer grade 3/4 adverse effects (47 versus 94 percent). The most common side effects with targeted therapy were pyrexia, headache, and vomiting. Overall survival data are not yet mature, with all but one patient alive at last follow-up.
Dabrafenib plus trametinib also has activity in the relapsed/refractory setting. In a four-part phase 1/2 trial that included 37 patients with BRAF V600E-mutant recurrent/progressive PLGGs who received combination therapy, the objective response rate was 25 percent, and combination therapy was better tolerated than trametinib monotherapy [62].
Other targeted therapies — Other therapies require further study or are relevant to uncommon subsets of PLGG.
●Everolimus – Everolimus, an mTOR inhibitor, was found to be well tolerated with some clinical efficacy in patients with multiply recurrent PLGG and is now being evaluated in combination with trametinib in recurrent low- and high-grade gliomas (NCT04485559) [65].
●Erdafitinib – Erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor, has been evaluated in patients with relapsed/refractory tumors harboring FGFR 1/2/3/4 alterations as part of the Pediatric MATCH trial (NCT03155620). In preliminary results, partial response or stable disease was observed in 54 percent of those on the arm with erdafitinib, which included several patients with PLGG [66]. However, FGFR inhibitors have been found to be associated with slipped capital femoral epiphyses and increased linear growth velocity when used in pediatric patients [67], and further study is needed.
●Other tyrosine kinase (TRK) inhibitors – While NTRK, ROS1, and ALK fusions are rare in PLGGs, TRK inhibitors (larotrectinib, entrectinib, and repotrectinib) have been associated with responses in patients with PLGGs treated in various tumor-agnostic clinical trials in children [68-70]. All three drugs are approved in the United States for use in pediatric and adult patients with NTRK fusion-positive solid tumors. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'TRK inhibitor activity'.)
Experience with these agents in children with high-grade gliomas is reviewed separately. (See "Infant-type hemispheric gliomas", section on 'Role of receptor tyrosine kinase inhibitors'.)
Challenges with targeted therapy — While the prospect of targeted therapy in the treatment of PLGG is promising and may mean more effective treatments with lower toxicity profiles, important unanswered questions and challenges remain.
The optimal duration of targeted therapies is unknown. There have been many cases in which tumors progress after discontinuation of therapy, though most seem to respond when rechallenged with the same therapy [21,71,72]. Another concern is the development of drug resistance in tumors and how to address resistance if it occurs.
Cost is also an important barrier. These therapies can be cost-prohibitive if not used within a clinical trial or supplied directly by the drug company.
Ongoing clinical trials — There are several ongoing multicenter clinical trials evaluating various targeted therapies. A searchable database of clinical trials is available through the United States National Library of Medicine. Some of the key trials in PLGG include:
●BRAF inhibitors:
•NCT05566795: LOGGIC/FIREFLY-2 – Randomized multicenter phase 3 trial to evaluate tovorafenib monotherapy versus standard-of-care chemotherapy in first-line PLGG harboring a RAF alteration.
●MEK inhibitors:
•NCT04166409: ACNS1833 – Randomized multicenter phase 3 study comparing selumetinib to standard chemotherapy (CV) as front-line therapy in patients newly diagnosed with non-NF1-associated PLGG.
•NCT03871257: ACNS1831 – Randomized multicenter phase 3 study comparing selumetinib to standard chemotherapy (CV) as frontline therapy in patients newly diagnosed with NF1-associated PLGG.
•NCT03363217: TRAM-01 – Nonrandomized multicenter phase 2 study of trametinib for patients with pediatric glioma of plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway.
•NCT04923126: SJ901 – Nonrandomized multicenter phase 1/2 study of mirdametinib in patients with both previously untreated and recurrent or progressive PLGG.
●Combination therapies:
•NCT04576117: COG ACNS1931 – Phase 3 multicenter trial evaluating selumetinib versus selumetinib plus vinblastine in recurrent or progressive non-NF1 PLGGs lacking BRAF V600E or IDH1 mutations.
•NCT02840409: Randomized multicenter phase 2 clinical trial evaluating the efficacy of vinblastine combined with bevacizumab as first-line therapy in PLGGs.
•NCT04485559: PNOC021 – Phase 1 multicenter trial evaluating the combination of trametinib and everolimus in recurrent or progressive low- and high-grade gliomas.
PROGNOSIS —
Overall survival (OS) for pediatric low-grade glioma (PLGG) is excellent, with 10-year OS exceeding 90 percent and 20-year OS up to 87 percent [2,27]. However, approximately 50 percent of tumors will progress or recur and require multiple treatment modalities or lines of therapy. As such, PLGGs are often viewed as a chronic disease that can result in significant morbidity. Patients with PLGGs can develop vision loss, endocrinopathies, neurocognitive dysfunction, seizures, and motor or sensory deficits, all of which can lead to poor functional outcomes and decreased quality of life.
The strongest clinical risk factor for worse outcomes is the inability to achieve complete surgical resection, which varies by location. Disseminated or metastatic disease, while uncommon, also confers poor prognosis. In a study of over 1000 PLGGs, 10-year progression-free survival (PFS) and OS for patients with PLGGs in the cerebellum were 89 and 99 percent, respectively, while disseminated disease was associated with 10-year PFS and OS of 0 and 67 percent, respectively [8].
Certain molecular features are also prognostic. PLGGs harboring either H3 K27M or combined BRAF V600E plus CDKN2A deletion behave more aggressively, invariably progress, and have a poorer prognosis (10-year OS approximately 40 percent) [8].
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary brain tumors".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: What are clinical trials? (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Pediatric low-grade gliomas (PLGGs) are the most common pediatric central nervous system (CNS) tumor. They include a range of specific tumors spanning World Health Organization (WHO) grade 1 and 2 gliomas, glioneuronal tumors, and neuronal tumors (table 4). (See 'Epidemiology' above and 'Specific tumor types' above.)
●Risk factors – Most PLGGs are sporadic. However, some are associated with a cancer predisposition syndrome, most notably neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC). (See 'Risk factors' above.)
●Pathology and molecular genetics – PLGGs almost universally involve aberrant activation of a single pathway, the RAS/mitogen-activated protein kinase (MAPK) pathway, and in most cases, a single-driver genetic alteration is identified (table 3). The most common mutations identified are BRAF alterations including BRAF V600E mutations, KIAA1549-BRAF fusion, and other non-canonical BRAF fusions, as well as FGFR alterations including mutations in FGFR1 or FGFR2/3. (See 'Histologic and molecular features' above.)
●Clinical features – Presenting signs and symptoms are highly dependent on tumor location (table 1) and patient age (table 2). Common symptoms include headache, vomiting, seizures, changes in vision, and fatigue. (See 'Signs and symptoms' above.)
PLGGs can occur anywhere in the brain or spine. The most common sites are cerebellum, diencephalon, and cerebral hemispheres. (See 'Tumor location' above.)
On MRI, most PLGGs are circumscribed, homogeneous masses that are hypointense on T1-weighted images, hyperintense on T2-weighted images, and associated with little to no surrounding edema (image 4 and image 3). (See 'Neuroimaging' above.)
●Diagnosis – Neuroimaging is not able to distinguish histologic grade and type of PLGG, and tissue is required for definitive diagnosis. The main exceptions are optic pathway glioma (OPG) and typical-appearing tectal glioma, which can be diagnosed with imaging alone. Biopsy is typically performed at the time of a definitive surgical procedure. (See 'Tissue diagnosis' above.)
●Management – Management of PLGGs is multimodal and, unless the tumor can be completely resected, usually requires use of cytotoxic chemotherapy, radiation therapy (RT), and/or targeted therapy. The goals of multidisciplinary care are to minimize treatment-related morbidities and maximize quality of life in addition to controlling the tumor.
•Surgery – For all patients with operable PLGGs, we recommend maximal safe resection (Grade 1B). Gross total resection is the goal and is curative in most cases. Tumors in the midline, optic pathway, and brainstem cannot be safely resected, and the main role of surgery is for tissue diagnosis and management of hydrocephalus, if present. (See 'Surgery' above and 'Monitoring after complete resection' above.)
•Residual/progressive tumors – The approach for many tumors is in flux, with rapid advances in molecular diagnostics and discovery of targetable pathway alterations. All treatment decisions involve shared decision-making, and multidisciplinary case discussions are invaluable. (See 'Residual/progressive tumors' above.)
Treatment selection is highly individualized and depends on the tumor type and molecular aberration (if present), clinical trial availability and interest, regulatory approval status and cost (for targeted therapies), and individual patient factors that influence the balance of risks and benefits (eg, tumor size, location, and patient age when considering RT; age and comorbidities when considering systemic therapies) (table 8). (See 'Specific therapies' above.)
●Prognosis – Overall survival (OS) in patients with PLGG is excellent, with nearly 90 percent of patients alive at 20 years after diagnosis. However, approximately 50 percent of tumors will progress or recur and require multiple treatment modalities or lines of therapy for control, leading to significant morbidity. (See 'Prognosis' above.)
