What is the standard management approach for glioblastoma?

Glioblastoma Management

For newly diagnosed glioblastoma, maximal safe surgical resection followed by concurrent radiotherapy (60 Gy) with temozolomide (75 mg/m² daily during radiation), then adjuvant temozolomide (150-200 mg/m² for 5 days every 28 days for 6 cycles) is the standard of care that improves overall survival. 1

Initial Diagnosis and Surgical Approach

MRI with gadolinium enhancement is the standard diagnostic modality for glioblastoma. 2 All patients should be transferred to a specialist neurosurgical center for evaluation. 3

Maximal safe surgical resection should be performed when technically feasible with low risk of permanent functional deterioration. 3 The goal is optimal cytoreductive surgery, as this improves survival outcomes. 2 If complete resection is not possible, histological confirmation via biopsy is mandatory before initiating adjuvant therapy. 3

Exceptions to Aggressive Surgical Approach

Surgery may not be appropriate for patients with: 3

• High physiological age with multiple comorbidities
• Poor performance status (low Karnofsky score)
• Multifocal lesions or tumors in critical functional zones
• Centrally located lesions with high surgical risk

In these select cases, biopsy is optional, and palliative radiotherapy or chemotherapy can be offered. 3

Standard Postoperative Treatment

Concomitant Phase (Stupp Protocol)

Begin treatment within one month of surgery. 3 The standard regimen includes: 1

• Radiotherapy: 60 Gy delivered in 30 fractions over 6 weeks, targeting the tumor bed/resection site with 2-3 cm margin 1
• Concurrent temozolomide: 75 mg/m² daily for 42 days (maximum 49 days), starting on the first day of radiotherapy and continuing through the last day 1

Critical: Pneumocystis pneumonia (PCP) prophylaxis is mandatory during the concomitant phase for all patients, regardless of lymphocyte count. 1 Continue prophylaxis until lymphocyte count recovers to ≤Grade 1. 1

Maintenance Phase

Starting 4 weeks after completing radiotherapy: 1

• Cycle 1: Temozolomide 150 mg/m² once daily for Days 1-5 of a 28-day cycle
• Cycles 2-6: If tolerated (ANC ≥1.5 × 10⁹/L and platelets ≥100 × 10⁹/L), increase to 200 mg/m² for Days 1-5 of each 28-day cycle 1
• Total duration: 6 cycles 1

This combined approach increases median survival by 2.5 months compared to radiotherapy alone (HR 0.63, p<0.0001). 1

Monitoring Requirements

Obtain complete blood counts: 1

• Prior to each dosing cycle
• On Day 22 (Day 29 for extended cycles) of each cycle
• Throughout treatment course

Liver function tests should be performed: 1

• At baseline
• Midway through the first cycle
• Prior to each subsequent cycle
• 2-4 weeks after the last dose

Monitor closely for lymphopenia and PCP, especially in patients receiving corticosteroids. 1

Management of Recurrent Glioblastoma

No standard treatment exists for recurrent glioblastoma; therapeutic options should be individualized based on performance status, tumor characteristics, and prior treatments. 4, 2

Surgical Re-Resection

Repeat cytoreductive surgery improves overall survival in selected patients. 2 Consider re-operation for patients with: 2

• Symptomatic but circumscribed relapses diagnosed ≥6 months after initial surgery
• Large symptomatic lesions causing mass effect
• Good performance status
• Possibility of gross total resection

Surgery earlier than 6 months after initial resection increases risk of operating on pseudoprogression and is unlikely to provide durable benefit. 2 The decision requires multidisciplinary consultation. 3, 2

Systemic Therapy Options

Lomustine (CCNU) is the standard chemotherapy with confirmed single-agent efficacy for recurrent glioblastoma. 4, 2 Alternative options include: 4, 2

• Temozolomide rechallenge: Consider in patients with MGMT promoter-methylated tumors who had prolonged interval since completing initial temozolomide 2
• Bevacizumab: Provides high response rates with steroid-sparing effect, though overall survival benefit remains uncertain 2
• Nitrosoureas: Can be used if not previously administered 4
• Local carmustine implants: Option for localized recurrence 4

Bevacizumab plus lomustine may improve progression-free survival but does not significantly improve overall survival and increases severe adverse events. 2

Targeted Therapies for Specific Mutations

Consider molecular testing to identify actionable mutations: 2

• BRAF V600E mutations: Dabrafenib/trametinib or vemurafenib
• TRK fusions: Larotrectinib or entrectinib
• ALK rearrangements: Lorlatinib or alectinib
• Hypermutant tumors: Immune checkpoint inhibitors (nivolumab or pembrolizumab)

Re-Irradiation

Re-irradiation may be considered for selected patients with small recurrent tumors using stereotactic radiotherapy or brachytherapy. 3, 2 However, the benefit remains uncertain due to limited prospective data. 2

Special Considerations

Anaplastic Astrocytoma (Grade 3)

Radiotherapy is the standard treatment. 4 Chemotherapy options include: 4

• Mono-drug chemotherapy with nitrosourea (BCNU)
• PCV (procarbazine, lomustine, vincristine)
• Temozolomide (demonstrated significant efficacy, level of evidence C) 4

Oligodendroglioma and Anaplastic Oligoastrocytoma

Radiotherapy is standard, with PCV chemotherapy showing proven efficacy. 4 The optimal timing of chemotherapy (neoadjuvant vs. adjuvant vs. at recurrence) remains undefined. 3 In selected patients with complete response to neoadjuvant chemotherapy, elderly patients, or those with large unresectable tumors, radiotherapy may be deferred. 3

Critical Pitfalls to Avoid

• Never omit PCP prophylaxis during concomitant temozolomide and radiotherapy - this is mandatory regardless of lymphocyte count 1
• Do not delay treatment beyond one month post-surgery - outcomes are time-sensitive 3
• Avoid re-operation within 6 months of initial surgery - high risk of pseudoprogression 2
• Monitor for myelosuppression closely - geriatric patients and women have higher risk 1
• Consider pseudoprogression if MRI changes occur within 6-9 months after radiotherapy - may require advanced imaging (amino acid PET) to distinguish from true progression 2

Palliative Care

For patients with poor performance status, large/multifocal lesions, or inability to consent, palliative care without aggressive anticancer treatment is appropriate. 2 Palliative regimens include oral etoposide, bevacizumab, or nitrosoureas. 2 Use corticosteroids for symptomatic cerebral edema with efforts to taper early. 2

Enrollment in clinical trials should be considered whenever possible for both newly diagnosed and recurrent glioblastoma. 3, 2