Role of Temozolomide in Pediatric Brain Tumors
For children ≥3 years with high-grade gliomas, temozolomide should be administered concurrently with radiation therapy followed by adjuvant temozolomide plus lomustine, as this regimen significantly improves both event-free and overall survival compared to temozolomide alone. 1
High-Grade Gliomas (Age ≥3 Years)
Preferred approach: Radiation therapy with concurrent temozolomide followed by adjuvant temozolomide + lomustine for 6 cycles after maximal surgical resection 1
The COG ACNS0423 trial (108 pediatric patients) demonstrated that this combination significantly improved outcomes:
- 3-year event-free survival: 22% vs 11% (temozolomide alone, p=0.019)
- 3-year overall survival: 28% vs 19% (temozolomide alone, p=0.019)
- Benefits were particularly notable in patients without gross total resection 1
Alternative option: Temozolomide without lomustine remains acceptable for adjuvant therapy, though outcomes are modestly inferior 1
Critical caveat: Despite these improvements, survival rates remain disappointingly low. The COG ACNS0126 study showed that temozolomide during and after radiation therapy failed to improve outcomes compared to historical controls, with 3-year event-free survival of only 11% 2. This underscores that while the addition of lomustine provides incremental benefit, the overall prognosis remains poor.
High-Grade Gliomas (Age <3 Years)
Chemotherapy alone is strongly recommended to avoid radiation-induced brain injury in this vulnerable age group 1
Recommended regimens include:
- Vincristine, carboplatin, and temozolomide
- Cyclophosphamide
- Vincristine, cisplatin, and etoposide 1
The Head Start II and III trials (32 children <6 years) using vincristine, carboplatin, and temozolomide followed by myeloablative chemotherapy showed:
- Children <3 years: 5-year event-free survival 44%, overall survival 63%
- Children 36-71 months: 5-year event-free survival 31%, overall survival 38%
- Children ≥72 months: 5-year event-free survival 0%, overall survival 13% 1
This demonstrates that younger children respond better to chemotherapy-based approaches, making radiation avoidance both safer and potentially more effective in this age group.
Low-Grade Gliomas
Temozolomide has limited and inconsistent efficacy in pediatric low-grade gliomas 3, 4
The COG phase 2 study showed:
- Only 1 partial response among 21 evaluable patients with low-grade astrocytoma
- However, 41% achieved stable disease through 12 courses 3
Important exception: A recent case report demonstrated marked tumor regression in treatment-refractory optic pathway glioma with malignant transformation using temozolomide combined with perampanel (an AMPA receptor antagonist). In vitro validation showed synergistic cytotoxicity, particularly in tumors with high GRIA1-4 expression in CD44-positive glioma stem-like cells 5. This represents a potential novel strategy, though it requires further validation.
Molecular Considerations
MGMT expression status significantly impacts temozolomide efficacy:
- Patients without MGMT overexpression: 2-year event-free survival 17%
- Patients with MGMT overexpression: 2-year event-free survival 5% (p=0.045) 2
BRAF V600E-mutated tumors (10-15% of pediatric high-grade gliomas): Consider targeted therapy with BRAF/MEK inhibitors (dabrafenib/trametinib or vemurafenib) rather than or in addition to temozolomide, as these show promising responses in case series 1
Safety Profile
Temozolomide toxicity in pediatric patients is similar to adults 6
Most common adverse reactions (COG study, N=122):
- Lymphopenia: 60% (Grade 3/4: 39%)
- Thrombocytopenia: 58% (Grade 3/4: 25%)
- Decreased WBC: 58% (Grade 3/4: 17%)
- Neutropenia: 51% (Grade 3/4: 20%)
- Nausea: 46% (Grade 3/4: 4%)
- Vomiting: 51% (Grade 3/4: 3%) 6
Serious but rare toxicities include: Prolonged pancytopenia potentially leading to aplastic anemia, hepatotoxicity, opportunistic infections (particularly Pneumocystis pneumonia requiring prophylaxis), and interstitial pneumonitis 6
Clinical Trial Enrollment
Clinical trial enrollment is the preferred option whenever available 1, as standard temozolomide-based regimens have failed to substantially improve the dismal prognosis of pediatric high-grade gliomas, and novel therapeutic approaches are urgently needed.
Practical Algorithm
- Age ≥3 years with high-grade glioma: Maximal safe resection → RT + concurrent temozolomide → adjuvant temozolomide + lomustine × 6 cycles
- Age <3 years with high-grade glioma: Maximal safe resection → chemotherapy alone (vincristine/carboplatin/temozolomide preferred)
- BRAF V600E-mutated: Consider targeted therapy with BRAF/MEK inhibitors
- Low-grade glioma: Temozolomide is not routinely recommended unless other options exhausted; consider for stable disease maintenance
- Recurrent disease: Temozolomide shows limited benefit; prioritize clinical trials or molecular-targeted approaches