What is the standard dosing, common side effects, and prognosis of Temozolomide (TMZ) in patients with gliomas, particularly glioblastoma multiforme (GBM)?

Temozolomide (TMZ) Dosing, Side Effects, and Prognosis in Gliomas

The standard dosing regimen for temozolomide (TMZ) in glioblastoma is 75 mg/m² daily during radiation therapy followed by adjuvant TMZ at 150-200 mg/m² for 5 days every 28 days for 6-12 cycles, with side effects including myelosuppression, fatigue, nausea, and vomiting, while prognosis varies significantly by molecular subtype with median survival of 14.6 months for newly diagnosed glioblastoma treated with TMZ plus radiation. 1

Standard Dosing Regimens by Glioma Type

Newly Diagnosed Glioblastoma (IDH-wildtype)

• Concurrent phase with radiation:

  • TMZ 75 mg/m² once daily during radiation therapy (60 Gy in 30 fractions over 6 weeks) 1
  • PCP prophylaxis required during this phase due to risk of lymphocytopenia 1, 2

• Adjuvant phase:

  • Initial cycle: 150 mg/m² once daily for 5 consecutive days every 28 days 1, 2
  • Subsequent cycles: May increase to 200 mg/m² if well tolerated (no grade >2 non-hematologic toxicity, ANC ≥1.5 x 10⁹/L, platelets ≥100 x 10⁹/L) 2
  • Duration: 6 cycles (standard) 1

IDH-Mutant Gliomas

• Lower-grade gliomas (Grade 2):

  • Adjuvant TMZ: 150-200 mg/m² once daily for 5 days every 28 days for up to 12 months 1

• Anaplastic gliomas (Grade 3):

  • Adjuvant TMZ: 150-200 mg/m² once daily for 5 days every 28 days for up to 12 months 1, 3

Elderly or Poor Performance Status Patients

• Option 1: Hypofractionated radiation with concurrent TMZ 75 mg/m² daily for 21 days, followed by adjuvant TMZ 150-200 mg/m² for 5 days every 28 days 1
• Option 2: TMZ monotherapy 100 mg/m² days 1-7 every 14 days or 200 mg/m² days 1-5 every 28 days 1, 4

Dose Modifications

• Hematologic toxicity thresholds requiring dose interruption:

  • ANC <1.0 x 10⁹/L
  • Platelets <50 x 10⁹/L 2

• Discontinuation criteria:

  • ANC <0.5 x 10⁹/L
  • Platelets <10 x 10⁹/L
  • Grade 3-4 non-hematologic toxicity 2

Common Side Effects

Hematologic

• Lymphopenia (most common)
• Thrombocytopenia
• Neutropenia
• Leukopenia 1, 2

Non-hematologic

• Alopecia (hair loss)
• Nausea and vomiting
• Headache
• Fatigue
• Anorexia
• Constipation
• Diarrhea 1, 3, 2

Serious Adverse Events

• Pneumocystis pneumonia (PCP) - prophylaxis required during concurrent phase
• Hepatotoxicity - monitor liver function tests at baseline, midway through first cycle, and before each subsequent cycle
• Potential for secondary malignancies including myelodysplastic syndrome and leukemia 2

Prognosis by Glioma Type

Glioblastoma (IDH-wildtype)

• With TMZ + radiation: Median survival 14.6 months
• With radiation alone: Median survival 12.1 months
• 2-year survival rate: 26.5% with TMZ + radiation vs 10.4% with radiation alone
• 5-year survival rate: 10% with TMZ + radiation vs 2% with radiation alone 1, 5

Anaplastic Gliomas

• IDH-mutant, 1p19q codeleted (oligodendroglioma): Best prognosis, median survival can exceed 9.5 years 1
• IDH-mutant, non-codeleted: Intermediate prognosis, median survival approximately 3 years 1
• IDH-wildtype: Poor prognosis, similar to glioblastoma (approximately 1.1 years) 1

Prognostic Factors

• MGMT promoter methylation: Significant predictor of response to TMZ

  • Methylated MGMT: Better response to TMZ (HR 0.56,95% CI 0.34-0.93)
  • Oligodendrogliomas frequently exhibit MGMT hypermethylation, explaining enhanced chemosensitivity 1

• IDH mutation status: Strong prognostic factor regardless of treatment 1

• 1p/19q codeletion: Associated with improved response to treatment and better overall survival 1, 3

Clinical Pearls and Pitfalls

• Complete blood counts should be monitored prior to each cycle and weekly if cytopenias develop
• TMZ should be taken on an empty stomach to reduce nausea and vomiting; bedtime administration may be helpful
• Capsules should be swallowed whole, not opened or chewed
• For patients who progress on standard TMZ regimen, alternative dosing schedules (continuous dose-intense TMZ 50 mg/m²/day) may provide benefit, particularly for those who progress after a treatment-free interval 6, 7
• TMZ appears to be safe in patients with BCNU wafer implants, despite initial concerns about interactions 1