What is the recommended treatment approach for a patient diagnosed with brain glioma?

Treatment Approach for Brain Glioma

All patients with suspected glioma should undergo maximal safe surgical resection at a specialized neurosurgical center, followed by molecular characterization of the tumor tissue to guide subsequent treatment with radiotherapy and temozolomide-based chemotherapy. 1

Initial Diagnostic Workup

Imaging and Tissue Acquisition:

• MRI with gadolinium contrast is the mandatory first-line imaging modality 1
• Clinical decision-making without tissue diagnosis should only occur in exceptional circumstances (e.g., patients with prohibitive surgical risk, extensive comorbidities, or rapid neurological deterioration with typical radiological appearance of glioblastoma) 1
• All patients should be transferred to a specialized neurosurgical center for biopsy or resection 1
• When open resection is not safely feasible due to tumor location or patient condition, stereotactic biopsy (frame-based or frameless) should be performed with serial sampling along the needle trajectory to minimize sampling bias 1

Molecular Testing Requirements: The following molecular markers must be assessed as they are critical for diagnosis, prognosis, and treatment decisions 2:

• IDH mutation status (disease-defining marker) 1, 2
• MGMT promoter methylation status (predicts temozolomide benefit) 1, 2, 3
• 1p/19q codeletion status (particularly for oligodendrogliomas) 1, 2
• Additional markers: TERT promoter mutations, EGFR amplification, chromosome 7 gain/10 loss 2

Surgical Management

Extent of Resection:

• Maximal safe surgical resection should be performed whenever technically feasible without causing permanent neurological deterioration 1, 4
• Gross total resection improves survival outcomes compared to subtotal resection or biopsy alone 2
• Use of 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery improves complete resection rates and progression-free survival 4
• Postoperative MRI or CT should be obtained within 24-48 hours (ideally within 72 hours) to assess extent of resection and distinguish residual tumor from postoperative changes 5, 6

Exceptions to aggressive resection: Patients with high physiological age, multiple comorbidities, poor performance status (low Karnofsky score), or tumors in eloquent/multifocal/centrally located areas where resection carries high risk of permanent deficit 1

Grade 3-4 (High-Grade) Glioma Treatment

Standard Postoperative Therapy

Radiotherapy (Standard of Care):

• Fractionated focal external-beam radiotherapy: 60 Gy in 30 fractions of 2 Gy each 1
• Treatment should begin within one month of surgery 1
• Target volume: tumor bed or resection site with 2-3 cm margin, defined using gadolinium-enhanced T1-weighted MRI 1, 6
• For elderly patients (>65 years) or those with poor performance status, hypofractionated regimens (e.g., 3 Gy × 10 fractions) are preferred 1, 4

Concurrent and Adjuvant Temozolomide (FDA-Approved Standard):

• Concurrent phase: Temozolomide 75 mg/m² daily throughout radiotherapy (typically 42 days, maximum 49 days), starting on the first day of RT 3, 6
• Adjuvant phase: Begin 4 weeks after completing RT 3
  • Cycle 1: 150 mg/m² daily for 5 consecutive days of each 28-day cycle 3, 6
  • Cycles 2-6: Increase to 200 mg/m² if well tolerated (ANC ≥1.5 × 10⁹/L and platelets ≥100 × 10⁹/L) 3, 6
  • Standard duration: 6 cycles, though additional cycles may be considered in partial responders 6
• This regimen significantly improves overall survival (HR 0.63, p<0.0001) and increases median survival by 2.5 months compared to radiotherapy alone 3

MGMT Methylation Status Considerations:

• MGMT promoter methylation predicts benefit from temozolomide therapy 1, 2, 3
• For elderly patients with methylated MGMT, temozolomide alone may be considered; for unmethylated MGMT, hypofractionated radiotherapy is preferred 4

Supportive Care During Treatment

Pneumocystis Pneumonia Prophylaxis:

• Required during concurrent chemoradiotherapy regardless of lymphocyte count, continuing until lymphocyte recovery to ≤Grade 1 3

Corticosteroid Management:

• Administer preoperatively to decrease symptomatic tumor-associated edema (unless primary CNS lymphoma or inflammatory lesions suspected) 1
• Use minimal effective dose with regular re-evaluation 1
• Taper as early as possible to minimize side effects (myopathy, hyperglycemia, opportunistic infections, psychiatric complications) 5, 4
• Methylprednisolone or prednisolone preferred as single morning doses 1

Anticonvulsant Therapy:

• Administer to patients who have experienced seizures 1
• Primary prophylaxis does NOT reduce risk of first seizure in seizure-naive patients 1
• Use single-drug therapy; consider enzyme-inducing effects on chemotherapy toxicity 1

Thromboembolism Prophylaxis:

• Low-molecular weight heparin and compression stockings for perioperative prevention 1
• Maintain surveillance for venous thrombotic events, which occur frequently in glioma patients 5, 4

Follow-Up Protocol

Imaging Schedule:

• MRI every 3-4 months is standard practice outside clinical trials 5, 4
• Contrast-enhanced MRI is the preferred modality 5

Critical Pitfall - Pseudoprogression:

• Enhancement and apparent tumor progression on imaging 4-8 weeks after completing radiotherapy may represent pseudoprogression (blood-brain barrier permeability changes) rather than true progression 1, 5
• Confirm with repeat MRI 4 weeks later before modifying treatment 5
• Complete at least 3 cycles of adjuvant temozolomide before discontinuing therapy due to apparent progression 6

Clinical Monitoring:

• Complete neurological examination at each visit 5
• Monitor for seizures, corticosteroid requirements, and venous thrombotic events 5, 4
• Evaluate response using Macdonald criteria (tumor size, neurological function, corticosteroid use) 5

Recurrent Disease Management

Treatment Options:

• Repeat surgical resection may prolong survival in selected patients with favorable factors (good performance status, accessible location) 1
• Re-irradiation can be considered with individualized dose/fractionation based on prior treatment, pattern of relapse, and functional status 7
• Chemotherapy shows benefit in patients with adequate performance status who have not received prior adjuvant cytotoxic therapy 1
• Anaplastic astrocytomas respond better to chemotherapy than glioblastomas 1
• For MGMT-methylated tumors, re-exposure to temozolomide may be considered 2
• Entry into clinical trials is strongly recommended for recurrent disease 6

Oligodendroglioma-Specific Considerations

• Patients with 1p/19q codeletion have longer survival and better chemotherapy response 1
• For recurrent oligodendroglioma, chemotherapy should be considered 1
• PCV regimen (procarbazine, lomustine, vincristine) is an option for anaplastic oligodendroglioma 1

Multidisciplinary Team Requirement

All glioma management decisions must involve a multidisciplinary neuro-oncology team including: 1, 6

• Neurosurgeons
• Neuroradiologists
• Neuropathologists
• Radiation oncologists
• Medical/neuro-oncologists
• Allied health professionals

This approach optimizes treatment outcomes and ensures comprehensive, patient-centered care throughout the disease course 8, 6, 9.