What is the classification and standard treatment of glioblastoma?

Glioblastoma Classification and Standard Treatment

Glioblastoma should be classified according to the most recent WHO Classification of Tumors of the Central Nervous System with molecular testing for IDH mutation status, MGMT promoter methylation, and other key genetic markers, followed by maximal safe surgical resection and concurrent radiotherapy with temozolomide, then adjuvant temozolomide. 1, 2

Classification of Glioblastoma

Integrated Histomolecular Classification

• Glioblastoma is classified as WHO grade 4, the highest grade in the WHO classification system 1
• Modern classification requires integration of histological features and molecular markers 1
• Key molecular markers that must be tested include:
  • IDH mutation status (IDH-wildtype vs. IDH-mutant) 1
  • MGMT promoter methylation status 1
  • 1p/19q codeletion status (for oligodendroglial tumors) 1
  • TERT promoter mutations 1
  • EGFR amplification 1
  • Chromosome 7 gain/chromosome 10 loss (+7/-10 signature) 1

Diagnostic Algorithm

• Immunohistochemistry for IDH1 R132H and nuclear ATRX expression should be performed routinely 1
• If IDH1 R132H immunohistochemistry is negative, sequencing of IDH1 codon 132 and IDH2 codon 172 should be conducted in patients <55 years 1
• For midline gliomas, H3 K27M status should be assessed 1
• MGMT promoter methylation testing is essential, particularly for elderly patients, to guide treatment decisions 1, 2

Standard Treatment of Glioblastoma

Surgical Management

• Maximal safe surgical resection is the initial approach whenever feasible 1, 3, 2
• Gross total resection improves survival outcomes compared to subtotal resection or biopsy 1, 2
• 5-aminolevulinic acid (5-ALA) can be used during surgery to improve extent of resection 3
• When resection is not safely feasible, a stereotactic biopsy should be performed to obtain tissue for diagnosis 3, 2

Radiotherapy

• Standard fractionated radiotherapy (60 Gy in 30 fractions of 2 Gy) is recommended after resection or biopsy 1, 2
• For elderly patients (>65-70 years) or those with poor performance status, hypofractionated regimens (e.g., 40 Gy in 15 fractions) are preferred 1, 3, 2
• Radiation should be targeted to the tumor bed plus a margin, not whole-brain radiation 2

Chemotherapy

• Concurrent and adjuvant temozolomide is the standard chemotherapy regimen 1, 2, 4
• The standard schedule for concurrent temozolomide is 75 mg/m² daily during radiotherapy 2
• Adjuvant temozolomide is typically administered at 150-200 mg/m² for 5 days every 28 days for 6-12 cycles 2
• MGMT promoter methylation status predicts benefit from temozolomide therapy 1, 2
• For elderly patients with MGMT promoter methylation, temozolomide alone may be considered 3, 2

Treatment Algorithm Based on Patient Factors

• For patients <70 years with good performance status:
  • Maximal safe resection + concurrent radiotherapy (60 Gy) with daily temozolomide + adjuvant temozolomide 1, 2
• For elderly patients (>70 years) with good performance status:
  • MGMT methylated: Consider temozolomide alone or hypofractionated RT with temozolomide 3, 2
  • MGMT unmethylated: Hypofractionated radiotherapy alone 3, 2
• For patients with poor performance status:
  • Best supportive care or hypofractionated radiotherapy (e.g., 5 × 5 Gy) 1, 3

Prognostic Factors

• Key favorable prognostic factors include:
  • Younger age (<50 years) 1, 2
  • Good performance status 1, 2
  • Extent of resection (gross total vs. subtotal) 1, 2
  • MGMT promoter methylation 1, 2
  • IDH mutation (rare in primary glioblastoma) 1, 2

Follow-up and Monitoring

• Clinical evaluation and MRI imaging every 3-4 months 3, 2
• Special attention to neurological function, seizures, and corticosteroid use 3
• Early tapering of steroids is recommended to minimize side effects 3
• Caution in interpreting imaging within first 3 months due to pseudoprogression 3, 2

Treatment of Recurrent Disease

• Consider surgical re-resection when feasible 2
• Bevacizumab may improve progression-free survival but not overall survival 2
• Re-exposure to temozolomide may be considered for MGMT-methylated tumors 1
• Tumor-treating fields (TTFields) remain controversial despite positive phase III trial results 1, 2

Despite advances in molecular classification and treatment strategies, glioblastoma remains a disease with poor prognosis, with median survival of approximately 15 months with standard treatment 2, 5.