What are the latest guidelines for the management of Glioblastoma multiforme (GBM)?

Management Guidelines for Glioblastoma Multiforme (GBM)

The standard of care for newly diagnosed glioblastoma multiforme includes maximal safe surgical resection followed by fractionated radiotherapy with concurrent and adjuvant temozolomide, which has been shown to improve overall survival and quality of life. 1

Initial Diagnosis and Assessment

• Gadolinium-enhanced MRI with diffusion-weighted imaging is the standard diagnostic tool for detecting glioblastoma 2
• Molecular testing should include:
  • MGMT promoter methylation status (guides treatment decisions, particularly in elderly patients) 1
  • IDH mutation status (for proper classification and management) 1
• Advanced imaging techniques such as amino acid PET may help distinguish true progression from treatment-related changes in cases of diagnostic uncertainty 2

Surgical Management

• Maximal safe tumor resection should be attempted whenever feasible as it:
  • Improves overall survival 1
  • Alleviates symptoms related to increased intracranial pressure 3
  • Decreases need for corticosteroids 3
  • Provides adequate tissue for pathologic diagnosis and molecular characterization 3
• Gross total resection is associated with better outcomes than subtotal resection, particularly in patients over 70 years 3
• When complete resection is not feasible, subtotal resection for tissue diagnosis and debulking should be considered, especially for symptomatic mass effect 3
• In cases where clinical benefit from cytoreduction is not feasible, biopsy is recommended 3

Radiation Therapy

For Patients <70 Years with Good Performance Status:

• Standard fractionated radiotherapy: 60 Gy in 2-Gy fractions over 6 weeks 1
• Partial-brain radiation therapy is the standard approach rather than whole-brain radiation 1

For Elderly Patients (≥65-70 Years):

• Hypofractionated accelerated course RT (completing treatment in 2-3 weeks) is recommended 3
• Typical fractionation schedules: 34 Gy/10 fractions or 40.05 Gy/15 fractions 3
• Short-course RT (40 Gy in 15 fractions over 3 weeks) has been shown to be effective and well-tolerated 3

Chemotherapy

• Concurrent temozolomide during radiation followed by adjuvant temozolomide is the standard regimen 1, 4
• For patients between 60-70 years, the addition of temozolomide concurrently with radiation therapy followed by at least 6 months of adjuvant temozolomide improves survival 3
• For patients ≥65 years with good performance status, short-course RT with concurrent and adjuvant temozolomide significantly improves OS and PFS compared to RT alone (median OS 9.3 vs 7.6 months) 3
• MGMT promoter methylation status should guide treatment decisions:
  • Patients with methylated MGMT promoter benefit most from temozolomide 3
  • For patients >64 years with methylated MGMT, temozolomide alone may be considered as it produces improved event-free survival over radiation alone 3

Management of Recurrent Disease (Progressive GBM)

• Cytoreductive surgery is recommended for symptomatic pGBM to improve overall survival 3
• Surgical resection should be considered for patients with:
  • Symptomatic but circumscribed relapses diagnosed at least 6 months after initial surgery
  • Large symptomatic lesions causing mass effect
  • Good performance status
  • Possibility of gross total resection 2
• Reirradiation should be considered as it provides improved local tumor control to maintain or improve neurological status and quality of life 3
• Reirradiation can be safely used in elderly patients 3
• Systemic therapy options include:
  • Lomustine as a standard treatment option with confirmed single-agent efficacy 2
  • Bevacizumab, which provides high response rates with a steroid-sparing effect, though it does not provide increased overall survival 3, 2
  • Temozolomide rechallenge in patients with MGMT promoter-methylated tumors who had a prolonged interval since completion of initial therapy 2

Prognostic Factors

• Favorable prognostic factors include:
  • Younger age (≤50 years) 1, 5
  • Good performance status (KPS >70) 1, 5
  • Extent of resection 1
  • MGMT promoter methylation 1
  • Absence of neurological deficits 5

Follow-up and Monitoring

• Clinical and imaging follow-up every 2-3 months is recommended 2, 1
• Regular MRI is the preferred imaging modality for surveillance after initial treatment 2, 1
• Pseudo-progression should be considered if MRI changes are noted within 6-9 months after radiotherapy 2

Special Considerations

• For BRAF V600E-mutated tumors, targeted therapies such as dabrafenib/trametinib or vemurafenib may be considered 2
• TRK fusion-positive tumors may respond to larotrectinib or entrectinib 2
• Hypermutant tumors may be candidates for immune checkpoint inhibitors 2
• Clinical trial enrollment should be considered whenever possible for patients with recurrent glioblastoma 2

Despite advances in treatment, the prognosis for GBM remains poor with median survival rates in the range of 8-12 months and 2-year survival rates of approximately 3-12% 6, 7, 8, 9.