What are the guidelines for using concurrent temozolomide (temozolomide) during external beam radiation therapy (EBRT) for grade 2-3 glioma?

Guidelines for Concurrent Temozolomide During EBRT for Grade 2-3 Glioma

Concurrent temozolomide (TMZ) during external beam radiation therapy (EBRT) is recommended for IDH-wildtype glioblastoma (grade 4) but is not standard for grade 2-3 gliomas, where the preferred approach is radiation followed by adjuvant chemotherapy based on molecular subtype. 1

Treatment Approach Based on Molecular Classification

IDH-Mutant Gliomas (Grade 2-3)

1. IDH-mutant, 1p19q codeleted oligodendrogliomas (Grade 2-3)

   • Standard treatment: Radiation followed by PCV polychemotherapy
   • Radiation dose:
     • Grade 2: 54 Gy in 30 fractions over 6 weeks 1
     • Grade 3: 59.4 Gy in 33 fractions at 5 fractions per week 1
   • No concurrent TMZ during radiation is recommended
   • Adjuvant chemotherapy: PCV is preferred over TMZ 1

2. IDH-mutant, 1p19q non-codeleted astrocytomas (Grade 2-3)

   • Standard treatment: Radiation followed by adjuvant chemotherapy
   • Radiation dose:
     • Grade 2: 54 Gy in 30 fractions over 6 weeks 1
     • Grade 3: 59.4 Gy in 33 fractions 1
   • No concurrent TMZ during radiation is recommended
   • Adjuvant chemotherapy:
     • Grade 2: PCV preferred 1
     • Grade 3: TMZ (150-200 mg/m² days 1-5 every 4 weeks for up to 12 months) 1

IDH-Wildtype Gliomas

For IDH-wildtype gliomas grade 2-3 that have molecular features of glioblastoma:

• Consider treating as per glioblastoma protocol with concurrent TMZ during radiation 1
• Concurrent TMZ dose: 75 mg/m² daily throughout radiation therapy 1, 2
• Followed by adjuvant TMZ: 150-200 mg/m² days 1-5 every 28 days for 6-12 cycles 1, 2

Dosing and Administration of Concurrent TMZ

When concurrent TMZ is used (primarily for IDH-wildtype gliomas with molecular features of glioblastoma):

• Concurrent phase: TMZ 75 mg/m² daily for the entire duration of radiotherapy (typically 42 days) 2
• Maintenance phase:
  • Cycle 1: 150 mg/m² once daily for 5 days followed by 23 days without treatment
  • Cycles 2-6: Can escalate to 200 mg/m² if toxicity is acceptable 2

Toxicity Management

• Complete blood count should be obtained weekly during concurrent treatment 2

• TMZ should be interrupted if:

  • Absolute neutrophil count ≥0.5 and <1.5 × 10⁹/L
  • Platelet count ≥10 and <100 × 10⁹/L
  • CTC non-hematological toxicity grade 2 2

• TMZ should be discontinued if:

  • Absolute neutrophil count <0.5 × 10⁹/L
  • Platelet count <10 × 10⁹/L
  • CTC non-hematological toxicity grade 3 or 4 2

Special Considerations

1. Elderly patients or those with poor performance status:

   • Consider hypofractionated radiation (40 Gy in 15 fractions) with concurrent TMZ (75 mg/m² daily for 21 days) 1, 3
   • This regimen has shown median survival of 11 months with acceptable toxicity 3

2. Pneumocystis pneumonia prophylaxis:

   • Required during concurrent TMZ and radiation
   • Continue until recovery from lymphocytopenia (CTC Grade ≤1) 2

Clinical Outcomes

The addition of concurrent TMZ to radiation therapy has demonstrated:

• Significant survival benefit in glioblastoma (14.6 vs 12.1 months) 4
• Acceptable toxicity profile with grade 3-4 hematologic toxicity in 7% of patients 4
• Two-year survival rate improvement from 10.4% to 26.5% 4

Important Caveats

1. The evidence for concurrent TMZ during EBRT specifically for grade 2-3 gliomas is limited, with most robust data coming from glioblastoma studies.

2. Treatment decisions should be based on molecular markers (IDH mutation, 1p/19q codeletion, MGMT methylation) rather than histological grade alone.

3. The benefit of concurrent TMZ during radiation is most established for IDH-wildtype gliomas with molecular features of glioblastoma, while for true IDH-mutant grade 2-3 gliomas, sequential therapy (radiation followed by adjuvant chemotherapy) remains standard.

4. Grade 3-4 hematologic toxicities occur in approximately 6-11% of patients receiving concurrent TMZ with radiation 5, 3, requiring careful monitoring.