Pediatric high-grade gliomas (pHGGs) are a group of tumors affecting approximately 0.85 children per 100,000 annually. The general outcome for these tumors is poor with 5-year survival rates of less than 20%. It is now recognized that these tumors represent a heterogeneous group of tumors rather than one entity. Large-scale genomic analyses have led to a greater understanding of the molecular drivers of different subtypes of these tumors and have also aided in the development of subtype-specific therapies. For example, for pHGG with NTRK fusions, promising new targeted therapies are actively being explored. Herein, we review the clinico-pathologic and molecular classification of these tumors, historical treatments, current management strategies, and therapies currently under investigation.

Pediatric hemispheric high-grade glioma: targeting the future.

Pediatric Neuro-Oncology.

This case study demonstrates that first-line treatment of a neurotrophic receptor tyrosine kinase (NTRK) fusion–positive infantile glioblastoma with larotrectinib, an NTRK inhibitor (NTRKi), was a safe and effective way to achieve tumor regression in our patient. An 18-month-old Saudi Arabian female presented with a history of right-sided weakness and partial seizures. Brain magnetic resonance imaging (MRI) revealed a large left frontal complex contrast-enhancing mass. Craniotomy for gross total resection (GTR) was performed, and histologic pathologic analysis revealed a diagnosis of glioblastoma. Postoperatively, the patient showed excellent recovery with no neurologic deficits. The tumor was then submitted for comprehensive genomic profiling. As a result of the expected poor survival, the patient’s family declined standard therapy, including chemotherapy and/or radiation therapy. Molecular analysis reported an ETV6-NTRK3 fusion, which can be targeted by larotrectinib, an oral tyrosine kinase (TRK) inhibitor. At the 3-month postresection follow-up, MRI showed local tumor recurrence. Given the results of molecular testing, the family agreed to initiate oral larotrectinib as a less invasive therapy. Follow-up MRI was performed 8 weeks after larotrectinib treatment and showed significant tumor regression, indicating a positive response to treatment with no reported adverse effects. This patient case highlights the importance of genomic profiling for pediatric brain tumors to identify targetable alterations. It further demonstrates the potential for TRK inhibitors as a first-line therapy for malignant pediatric brain tumors harboring TRK fusions.

Regression of ETV6-NTRK3 Infantile Glioblastoma After First-Line Treatment With Larotrectinib

Pediatric high-grade glioma is a rare tumor characterized by high mortality. The authors report the first case of a high-grade glioma associated with a GOPC(FIG)-ROS1 fusion in a pediatric patient. The patient underwent gross-total resection at the age of 4 years, followed by adjuvant high-dose chemotherapy and autologous hematopoietic stem cell rescue. At 30 months after transplantation, she remains disease free.

/pdf/novel-gopc-fig-ros1-fusion-in-a-pediatric-high-grade-glioma-47dstzsl2o.pdf

Novel GOPC(FIG)-ROS1 fusion in a pediatric high-grade glioma survivor

Central nervous system (CNS) cancers account for approximately one quarter of all pediatric tumors and are the leading cause of cancer-related death in children. More than 4,000 brain and CNS tumors are diagnosed each year in children and teens, and the incidence rate has remained stagnant in recent years. The most common malignant pediatric CNS tumors are gliomas, embryonal tumors consisting of predominately medulloblastomas, and germ cell tumors. The inaugural version of the NCCN Guidelines for Pediatric Central Nervous System Cancers focuses on the diagnosis and management of patients with pediatric diffuse high-grade gliomas. The information contained in the NCCN Guidelines is designed to help clinicians navigate the complex management of pediatric patients with diffuse high-grade gliomas. The prognosis for these highly aggressive tumors is generally poor, with 5-year survival rates of <20% despite the use of combined modality therapies of surgery, radiation therapy and systemic therapy. Recent advances in molecular profiling has expanded the use of targeted therapies in patients whose tumors harbor certain alterations. However, enrollment in a clinical trial is the preferred treatment for eligible patients.

Pediatric Central Nervous System Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Purpose

To report the final analysis of survival outcomes for children with newly diagnosed high-grade glioma (HGG) treated on the “Head Start” (HS) II and III protocols with chemotherapy and intent to avoid irradiation in children <6 years old.



Patients and Methods

Between 1997 and 2009, 32 eligible children were enrolled in HS II and III with anaplastic astrocytoma (AA, n = 19), glioblastoma multiforme (GBM, n = 11), or other HGG (n = 2). Central pathology review was completed on 78% of patients. Patients with predominantly brainstem tumors were excluded. Patients were to be treated with single induction chemotherapy regimen C, comprising four cycles of vincristine, carboplatin, and temozolomide. Following induction, patients underwent marrow-ablative chemotherapy and autologous hematopoietic cell rescue. Irradiation was used for patients with residual tumor after consolidation or >6 years old or at the time of tumor progression.



Results

The 5-year event-free survival (EFS) and overall survival (OS) for all HGG patients were 25 ± 8% and 36 ± 9%, respectively. The EFS at 5 years for patients with AA and GBM were 24 ± 11% and 30 ± 16%, respectively (P = 0.65). The OS at 5 years for patients with AA and GBM was 34 ± 12% and 35 ± 16%, respectively (P = 0.83). Children 72 months old (0% and 13 ± 12%).



Conclusions

Irradiation-avoiding treatment strategies should be evaluated further in young children with HGG given similar survival rates to older children receiving standard irradiation-containing therapies.

Outcome of young children with high-grade glioma treated with irradiation-avoiding intensive chemotherapy regimens: Final report of the Head Start II and III trials

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Outcome of young children with high-grade glioma treated with irradiation-avoiding intensive chemotherapy regimens: Final report of the Head Start II and III trials