What are the evidence-based management guidelines for recurrent glioblastoma?

Evidence-Based Management Guidelines for Recurrent Glioblastoma

For recurrent glioblastoma, treatment should be individualized based on patient factors with surgical resection recommended for eligible patients, followed by systemic therapy with lomustine or bevacizumab, while clinical trial enrollment should be prioritized whenever possible. 1

Diagnosis and Assessment

• Gadolinium-enhanced MRI with diffusion-weighted imaging is recommended as the standard diagnostic tool for detecting recurrent glioblastoma 1
• Pseudo-progression should be considered if MRI changes are noted within 6-9 months after radiotherapy; this requires careful evaluation to avoid unnecessary interventions 1
• Distinguishing between true progression and treatment-related changes may require advanced imaging techniques such as amino acid PET in cases of diagnostic uncertainty 1
• Regular follow-up with MRI every 2-3 months is recommended for surveillance after initial treatment 1

Surgical Management

• Repeat cytoreductive surgery is recommended to improve overall survival in selected patients with recurrent glioblastoma 1
• Surgical resection should be considered for patients with:
  • Symptomatic but circumscribed relapses diagnosed at least 6 months after initial surgery 1
  • Large symptomatic lesions causing mass effect 1
  • Good performance status 1
  • Possibility of gross total resection 1
• Second surgery earlier than 6 months after initial surgery increases the risk of intervention based on pseudoprogression and is unlikely to provide durable benefit 1
• The decision for re-operation should only be made after multidisciplinary consultation 1

Systemic Therapy Options

• Lomustine (CCNU) is considered a standard treatment option for recurrent glioblastoma with confirmed single-agent efficacy 1, 2
• Bevacizumab (10 mg/kg IV every 2 weeks) is FDA-approved for recurrent glioblastoma 3 and provides high response rates with a steroid-sparing effect, though the effect on overall survival remains uncertain 1
• Bevacizumab plus lomustine combination may improve progression-free survival compared to lomustine alone but does not significantly improve overall survival and increases the risk of severe adverse events 1, 4
• Regorafenib may improve overall survival compared to lomustine based on recent evidence, though more data is needed 4
• Temozolomide rechallenge may be considered in patients with MGMT promoter-methylated tumors who had a prolonged interval since completion of initial temozolomide therapy 1, 2
• Nitrosourea-based regimens are options for patients who have not received them previously 1

Radiation Therapy

• Re-irradiation may be considered for selected patients with small recurrent tumors using different modalities (brachytherapy, stereotactic radiotherapy) 1, 4
• The benefit of re-irradiation remains uncertain due to limited prospective and comparative trials 1
• When considering re-irradiation, tumor size, location, time since previous radiation, and patient performance status should be evaluated 4, 5

Novel Approaches and Targeted Therapies

• BRAF V600E-mutated tumors may benefit from targeted therapies such as dabrafenib/trametinib or vemurafenib 1
• TRK fusion-positive tumors may respond to larotrectinib or entrectinib 1
• Hypermutant tumors may be candidates for immune checkpoint inhibitors such as nivolumab or pembrolizumab 1
• ALK rearrangement-positive tumors may benefit from lorlatinib or alectinib 1
• Randomized trials have failed to demonstrate measurable anti-tumor efficacy of EGFR inhibition by erlotinib or PDGFR inhibition by imatinib in unselected patient populations 1

Palliative Care Considerations

• Palliative and best supportive care should be considered for patients with:
  • Poor performance status 1
  • Large or multifocal lesions 1
  • Inability to consent to treatment 1
  • Cases where aggressive therapy is unlikely to provide meaningful survival benefit 1
• Recommended regimens for palliation include oral etoposide, bevacizumab, or nitrosoureas (lomustine or carmustine) 1
• Corticosteroids may be used to manage symptomatic cerebral edema, with efforts to taper as early as possible 1

Clinical Trial Participation

• Enrollment in clinical trials should be prioritized whenever possible for patients with recurrent glioblastoma 1, 4
• Consider phase 0 or preoperative clinical trials before resection when available 1
• Molecular testing of tumor tissue may help determine eligibility for targeted therapy trials 1, 6

Treatment Algorithm

1. Confirm true progression (vs. pseudoprogression) with appropriate imaging
2. Assess patient factors: age, performance status, tumor location, molecular markers
3. Consider surgical resection if tumor is symptomatic, localized, and patient has good performance status
4. For eligible patients post-surgery or those not suitable for surgery:
   • Enroll in clinical trial if available
   • Consider systemic therapy with lomustine, bevacizumab, or targeted therapy based on molecular profile
   • Consider re-irradiation for small, well-defined tumors
5. For patients with poor prognostic factors, focus on palliative care and quality of life