What is the role of maintenance temozolomide in the treatment of pediatric thalamic glioma?

Maintenance Temozolomide in Pediatric Thalamic Glioma

Maintenance temozolomide should not be routinely used in pediatric thalamic glioma, as the evidence shows no survival benefit and these tumors—particularly K27M-mutant diffuse midline gliomas—have uniformly poor outcomes with benefits from treatment beyond radiotherapy remaining unestablished.

Understanding Pediatric Thalamic Gliomas

Molecular Classification and Prognosis

• Pediatric thalamic gliomas are predominantly K27M-mutant diffuse midline gliomas (WHO grade 4), which have uniformly poor prognosis and limited treatment options beyond radiotherapy 1
• The MGMT promoter is usually unmethylated in these tumors, which predicts poor response to temozolomide chemotherapy 1
• These tumors have not been studied in dedicated trials due to their rarity, and benefits from treatment options beyond radiotherapy have not been established 1

Evidence Against Maintenance Temozolomide

Pediatric High-Grade Glioma Data

• A multi-institutional study of 31 pediatric patients (45% with thalamic tumors) receiving 6 cycles of maintenance temozolomide after radiotherapy showed dismal outcomes: 2-year progression-free survival of only 11% and overall survival of 21% 2
• The addition of 6 cycles of temozolomide after radiotherapy did not alter the poor outcome of these patients compared to historical controls 2
• The median age was 12.3 years, with most patients having limited surgical options (45% biopsy only), reflecting the typical presentation of thalamic gliomas 2

Safety Concerns in Pediatric Population

• Secondary hematological malignancies occur in 7.7% of pediatric high-grade glioma patients at 10 years, with risk increasing to 20% when temozolomide is used as second-line therapy following multiagent chemotherapy 3
• While first-line temozolomide alone did not show increased risk in 194 patients, the cumulative toxicity burden is concerning given the poor survival outcomes 3

Current Treatment Recommendations

Standard Approach for Pediatric Thalamic Glioma

• Radiotherapy remains the primary treatment modality for symptom control in pediatric thalamic gliomas, regardless of age 1
• Intensity-modulated radiotherapy or 3D conformal radiotherapy should be used at standard doses without escalation 1
• Dose-escalated radiotherapy and concurrent or adjuvant systemic therapy have produced disappointing results in pontine diffuse midline gliomas, and this applies to thalamic locations as well 1

When Chemotherapy May Be Considered

• For children <3 years where radiotherapy should be avoided due to neurotoxicity risk, chemotherapy alone with regimens such as cyclophosphamide/vincristine or vincristine/carboplatin/temozolomide may be reasonable 1
• For older children with high-grade thalamic gliomas where some resection is possible, the COG ACNS0423 regimen (radiotherapy with concurrent temozolomide followed by adjuvant temozolomide plus lomustine for 6 cycles) showed modest improvement over temozolomide alone (3-year OS 28% vs 19%) 1

Alternative to Standard Maintenance

• If maintenance chemotherapy is pursued despite limited evidence, the combination of temozolomide plus lomustine is preferred over temozolomide alone based on the ACNS0423 trial showing superior event-free survival (22% vs 11% at 3 years) 1

Critical Caveats

Molecular Testing Imperative

• MGMT promoter methylation status should be assessed, as temozolomide activity is largely limited to MGMT-methylated tumors 1
• K27M mutation status should be confirmed, as this defines a distinct entity with poor prognosis where chemotherapy benefits are unproven 1

Clinical Trial Priority

• Given the poor outcomes and lack of established effective treatments, enrollment in appropriate clinical trials should be strongly considered over standard maintenance temozolomide 1
• Targeted therapies for specific molecular alterations (such as BRAF V600E mutations if present) may offer better options than cytotoxic chemotherapy 1

Palliative Care Focus

• For patients with pontine or thalamic diffuse midline gliomas whose tumors progress following initial radiotherapy, palliative reirradiation for symptom control and quality of life should be prioritized over additional chemotherapy 1
• The focus should shift to supportive and palliative care given the uniformly poor prognosis of these tumors 1