What is the recommended treatment regimen for Temozolomide (temozolomide) in a patient diagnosed with Glioblastoma Multiforme (GBM)?

Temozolomide Treatment Regimen for Glioblastoma Multiforme

For newly diagnosed GBM patients under age 70 with good performance status, the standard treatment is concurrent temozolomide at 75 mg/m² daily throughout 6 weeks of radiotherapy (60 Gy in 30 fractions), followed by adjuvant temozolomide at 150-200 mg/m² for 5 consecutive days every 28 days for 6 cycles. 1, 2, 3

Standard Regimen (Age <70 years, Good Performance Status)

Concurrent Phase:

• Temozolomide 75 mg/m² orally daily for 42 consecutive days (including weekends) during radiotherapy 2, 3
• Radiotherapy: 60 Gy delivered as 2 Gy fractions, 5 days per week over 6 weeks 1, 2
• Mandatory PCP prophylaxis throughout concurrent therapy and until lymphocytopenia recovers to Grade ≤1 2

Maintenance Phase (begins 4 weeks after completing concurrent therapy):

• Cycle 1: Temozolomide 150 mg/m² once daily for 5 consecutive days every 28 days 2, 3
• Cycles 2-6: Increase to 200 mg/m² if no significant toxicity occurred in Cycle 1 2, 3
• Continue for 6 cycles total 1, 2

This regimen improved median survival from 12.1 to 14.6 months and 2-year survival from 10.4% to 26.5% compared to radiotherapy alone (HR 0.63, P<0.001) 2.

Modified Regimen for Elderly Patients (Age ≥65 years)

For patients aged 65-70 years with good performance status, use the standard regimen above. 1 However, for patients over 70 years or those with poor performance status, hypofractionated radiotherapy with temozolomide is preferred 1:

Concurrent Phase:

• Temozolomide 75 mg/m² daily for 21 consecutive days 2
• Hypofractionated radiotherapy: 40 Gy in 15 fractions over 3 weeks (or 34 Gy in 10 fractions) 1

Maintenance Phase:

• Temozolomide 150-200 mg/m² for 5 consecutive days every 28 days 1, 2
• Continue for up to 12 cycles (rather than 6) in elderly patients 1, 2

This approach improved median OS from 7.6 to 9.3 months and PFS from 3.9 to 5.3 months in patients ≥65 years (P<0.0001) 1.

MGMT-Guided Treatment Decisions

MGMT promoter methylation status should guide treatment intensity, particularly in elderly patients 1, 2:

• MGMT methylated tumors: Derive substantial benefit from temozolomide; use combined chemoradiotherapy as above 1
• MGMT unmethylated tumors in elderly/poor performance patients: Consider hypofractionated radiotherapy alone 1
• Standard-risk patients <70 years: Use temozolomide regardless of MGMT status 2

The benefit from temozolomide is largely limited to MGMT promoter-methylated tumors, though current guidelines support its use in younger patients with good performance status regardless of methylation status 1, 2.

Temozolomide Monotherapy Option

For elderly patients unsuitable for combined modality treatment (particularly those with MGMT methylated tumors), temozolomide monotherapy is an alternative 1, 2:

• 200 mg/m² once daily for 5 consecutive days every 28 days for up to 6 cycles 2
• Alternative: 100 mg/m² once daily on days 1-7 every 2 weeks until progression 2

Temozolomide alone is non-inferior to radiotherapy alone in patients >64 years, with improved event-free survival in MGMT methylated tumors 1.

Critical Safety Monitoring

Hematologic toxicity is the primary concern:

• Grade 3-4 thrombocytopenia occurs in 15-20% of patients and can be severe and prolonged 4
• Women appear at higher risk (25% vs 14% in men) 4
• Median duration of severe thrombocytopenia is 32 days (range 1-389 days) 4
• 10% of patients may require platelet transfusions, with some requiring ongoing support for >6 months 4
• Monitor CBC weekly during concurrent phase and before each maintenance cycle 2

Grade 3-4 neutropenia occurs in 6-10% during concurrent therapy, with rare but serious infections including Pneumocystis pneumonia 5, 4. This mandates PCP prophylaxis 2.

Common Pitfalls to Avoid

• Do not skip PCP prophylaxis during concurrent therapy—two severe P. carinii infections occurred in early trials 5
• Do not empirically escalate temozolomide doses beyond standard dosing without strong justification, given the risk of irreversible thrombocytopenia 4
• Do not continue temozolomide through severe thrombocytopenia—17% of patients require treatment discontinuation 4
• Do not use prophylactic antiepileptic drugs in asymptomatic patients 6
• Recognize pseudoprogression (occurs in 8% of patients within 3 months post-radiotherapy) before discontinuing effective therapy 7, 6