What is the standard management for a newly diagnosed high‑grade glioma (WHO grade III or IV, most commonly glioblastoma) in an adult patient without contraindicating comorbidities?

High-Grade Glioma Management

Initial Surgical Approach

For newly diagnosed high-grade glioma (WHO grade III or IV), maximal safe surgical resection should be performed at a specialized center, followed by postoperative radiotherapy at 60 Gy in 1.8-2 Gy fractions combined with concurrent and adjuvant temozolomide. 1, 2, 3

Surgical Decision Algorithm

• Transfer to a specialized neurosurgical center for evaluation of operability criteria 1
• Pursue maximal safe resection as the standard approach, as extent of resection correlates with survival 1, 3, 4
• Perform biopsy only if optimal resection is not feasible due to:
  • High physiological age
  • Multiple comorbidities
  • Poor performance status (low Karnofsky score)
  • Multifocal lesions or tumors in eloquent/central brain regions 1

Postoperative Imaging

• Obtain MRI within 24-48 hours after surgery to distinguish residual tumor from postoperative edema and establish a baseline for future surveillance 5

Postoperative Treatment by Histologic Subtype

Glioblastoma (WHO Grade IV)

Concomitant Phase:

• Radiotherapy: 60 Gy delivered in 30 fractions (2 Gy per fraction) to the tumor bed with 2-3 cm margin 1, 2
• Concurrent temozolomide: 75 mg/m² daily for 42 days during radiotherapy 2, 6
• Pneumocystis pneumonia prophylaxis is mandatory during concurrent therapy and should continue until lymphocyte recovery to Grade ≤1 2

Maintenance Phase:

• Begin 4 weeks after completing radiotherapy 2
• Cycle 1: Temozolomide 150 mg/m² daily for 5 days, then 23 days rest 2
• Cycles 2-6: Escalate to 200 mg/m² daily for 5 days if ANC ≥1.5 × 10⁹/L, platelets ≥100 × 10⁹/L, and non-hematologic toxicity Grade ≤2 2
• Total duration: 6 cycles of maintenance therapy 2, 6

This regimen improved overall survival from 12.1 to 14.6 months and 6-month progression-free survival from 36.4% to 53.9% compared to radiotherapy alone 6

Anaplastic Astrocytoma (WHO Grade III)

Treatment depends on molecular profile:

• IDH-mutant, 1p19q non-codeleted:

  • Radiotherapy 59.4 Gy in 33 fractions (1.8 Gy each) 7
  • Adjuvant temozolomide is preferred: 150-200 mg/m² days 1-5 every 4 weeks for maximum 12 months 7
  • PCV is a Category 2A alternative (procarbazine 60 mg/m² days 8-21, lomustine 110 mg/m² day 1, vincristine 1.4 mg/m² IV days 8 and 29, in 8-week cycles for 6 cycles) 7

• Without molecular testing (older guidelines):

  • Radiotherapy is standard 1
  • Either nitrosourea monotherapy (BCNU) or PCV regimen 1

Anaplastic Oligodendroglioma/Oligoastrocytoma (WHO Grade III)

Molecular testing is critical for treatment decisions:

• IDH-mutant, 1p19q-codeleted (Category 1 recommendation):

  • Radiotherapy 59.4 Gy in 33 fractions 7
  • Adjuvant PCV using standard dosing (as above) 7
  • This combination provides significant survival benefit (HR 0.56 for overall survival; HR 0.21 specifically in 1p19q-codeleted tumors) 7

• Timing of chemotherapy (neoadjuvant vs. adjuvant vs. at recurrence) remains undefined, though adjuvant is most commonly used 1

• Selected patients (elderly, large unresectable tumors, complete response to neoadjuvant chemotherapy) may defer radiotherapy 1

Critical Supportive Care Measures

Thromboembolism Prophylaxis

• Perioperative prophylaxis with low-molecular-weight heparin and compression stockings is recommended 1
• Therapeutic anticoagulation can be safely initiated 4-5 days post-surgery if thromboembolic complications occur 1
• Ongoing surveillance for venous thromboembolism is essential, as it occurs frequently in glioma patients, especially with residual or recurrent tumor 8, 5

Corticosteroid Management

• Taper dexamethasone as early as clinically feasible to reduce infection risk 8
• Never abruptly discontinue due to risk of adrenal insufficiency 8
• Provide stress-dose steroids for surgical procedures 8
• Monitor for long-term complications: myopathy, hyperglycemia, opportunistic infections, psychiatric effects 5

Hematologic Monitoring

• During concurrent phase: Weekly complete blood counts 2
• During maintenance: CBC on day 22 of each cycle (or within 48 hours) and weekly until ANC >1.5 × 10⁹/L and platelets >100 × 10⁹/L 2
• Do not start next cycle until blood counts recover to these thresholds 2

Surveillance Protocol

Imaging Schedule

• MRI every 3-4 months is standard practice 5, 9
• Contrast-enhanced MRI is the preferred modality for response evaluation 5

Pseudoprogression Pitfall

• Enhancement 4-8 weeks post-radiotherapy may represent pseudoprogression (blood-brain barrier changes, not true progression) 5
• Confirm with repeat MRI 4 weeks later before changing treatment 5
• This is a critical distinction to avoid premature abandonment of effective therapy

Clinical Monitoring

• Complete neurological examination at each visit 5
• Seizure monitoring 5
• Corticosteroid dose tracking with goal of ongoing reduction 5
• Response evaluation using Macdonald criteria (tumor size, neurological function, corticosteroid use) 5

Treatment Modifications for Poor Performance Status

For patients with high physiological age, multiple comorbidities, poor functional status, or multifocal/eloquent location tumors:

• No standard treatment exists 1
• Options include:
  • Transfer to specialized center for expert evaluation
  • Radiotherapy alone
  • Chemotherapy alone
  • Palliative care without tumor-directed therapy 1
• Biopsy and surgery may be omitted in this population 1

Recurrent Disease Management

Five therapeutic options exist (no single standard): 1

• Re-resection (after multidisciplinary consultation) 1
• Systemic chemotherapy (bevacizumab or dose-intense temozolomide for glioblastoma) 3
• Local chemotherapy (carmustine wafer implants) 6
• Second-line radiotherapy (stereotactic techniques, brachytherapy) 1
• Palliative care without anticancer treatment 1

Bevacizumab is FDA-approved for recurrent glioblastoma but does not improve overall survival 3, 6

Additional FDA-Approved Options

• Tumor Treating Fields (TTFields) is the only treatment showing survival benefit beyond standard temozolomide (20.5 vs. 15.6 months overall survival; 56% vs. 37% 6-month progression-free survival) when added to maintenance temozolomide 6
• Lomustine, intravenous carmustine, and carmustine wafers are FDA-approved primarily for recurrent disease 6

Common Pitfalls to Avoid

• Do not delay treatment while awaiting molecular testing in glioblastoma; begin standard radiotherapy plus temozolomide and adjust later if needed
• Do not continue temozolomide during concurrent phase if ANC <1.5 × 10⁹/L or platelets <100 × 10⁹/L 2
• Do not misinterpret pseudoprogression as treatment failure; always confirm with repeat imaging 5
• Do not neglect PCP prophylaxis during concurrent chemoradiotherapy 2
• For PCV regimen: Grade 3/4 hematologic toxicity occurs in 56% of patients, with 20% discontinuing due to toxicity; close monitoring is essential 7